The Predictive Value of Peripheral Blood CD4+/CD8+ Ratio and NLR for Short-term Efficacy of Neoadjuvant Chemotherapy Combined with Immunotherapy in Locally Advanced Esophageal Cancer

The Predictive Value of Peripheral Blood CD4+/CD8+ Ratio and NLR for Short-term Efficacy of Neoadjuvant Chemotherapy Combined with Immunotherapy in Locally Advanced Esophageal Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Predictive Value of Peripheral Blood CD4+/CD8+ Ratio and NLR for Short-term Efficacy of Neoadjuvant Chemotherapy Combined with Immunotherapy in Locally Advanced Esophageal Cancer Mingjian Sheng, Yang Xiang, Jiming Yang, Li Chen, Tianyang Zeng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7114130/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The neutrophil-to-lymphocyte ratio (NLR) and peripheral blood lymphocyte subpopulations are indicators that can reflect the immune status and the degree of chronic inflammation in the human body. This study aims to investigate the predictive value of the peripheral blood CD4+/CD8+ ratio and NLR in assessing the short-term efficacy of neoadjuvant chemotherapy combined with immunotherapy in patients with locally advanced esophageal cancer.In this research, we compared the differences in lymphocyte subpopulations and NLR between patients achieving pathological complete response (pCR) and those who did not, as well as between those with radiographic remission (CR/PR) and those without (PD/SD) prior to treatment. The analysis revealed that patients with a high CD4+/CD8+ ratio and a low NLR were more likely to achieve pCR (P 0.05).These findings suggest that these biomarkers could be useful in predicting the effectiveness of the treatment in esophageal cancer patients, facilitating more precise and personalized therapeutic strategies. Chemoimmunotherapy Esophageal squamous cell carcinoma (ESCC) Pathological response Radiographic response CD4+/CD8+ ratio NLR Figures Figure 1 Introduction Currently, esophageal cancer is one of the most common malignant tumors worldwide. Approximately 78% of esophageal cancer cases occur in Asia, with China accounting for 49% of the cases [3-4] .China is a high-incidence region for esophageal cancer. Although the incidence and mortality rates have generally declined with economic development and improved living standards, certain areas still see esophageal cancer posing a significant threat to public health. These regional disparities may be related to economic factors and dietary habits in different parts of China. The pathological types of esophageal cancer include squamous cell carcinoma, adenocarcinoma, and basal cell carcinoma, among which squamous cell carcinoma is the most common type of esophageal malignant tumor in China [5] .With advancements in modern biomedical technology, the survival rates of cancer patients have improved, along with better prognoses and quality of life. The treatment approach for esophageal cancer has evolved from traditional chemotherapy to neoadjuvant chemoradiotherapy, and now to combined immunotherapy, providing greater benefits to patients. Currently, preoperative neoadjuvant therapy, surgery, and postoperative chemoradiotherapy are the mainstays of esophageal cancer treatment. For some early-stage patients, endoscopic therapy may be an option, while those with locally advanced disease often undergo neoadjuvant therapy first, followed by an assessment to determine the suitability for surgery. According to the international staging system (AJCC 8th edition), neoadjuvant chemoradiotherapy is becoming increasingly common in patients with stage IIB or stage III esophageal cancer [6] .In recent years, neoadjuvant chemotherapy has significantly improved the overall survival of patients with locally advanced esophageal cancer. The current neoadjuvant chemotherapy regimens for these patients include combinations such as paclitaxel with platinum-based agents, cisplatin with fluorouracil or capecitabine, or tegafur-based therapies [7] .Currently, immunotherapy is increasingly being utilized in the treatment of esophageal cancer. The combination of pembrolizumab or nivolumab with chemotherapy has been approved by the European Medicines Agency as a first-line treatment for esophageal squamous cell carcinoma (ESCC) with high PD-L1 expression. Clinical studies have also confirmed that combining immunotherapy with chemotherapy offers greater therapeutic benefits compared to chemotherapy alone [8] .Patients who undergo neoadjuvant chemotherapy combined with immunotherapy have demonstrated improved survival outcomes. However, it is important to recognize that only a limited subset of esophageal cancer patients may benefit from this combined treatment approach. Therefore, identifying reliable biomarkers to distinguish responders from non-responders is crucial. Previous studies have shown that tumor-associated immune responses are closely linked to tumor development, progression, and patient prognosis. Currently, it is understood that cellular immunity plays a dominant role in the immune response against tumors, with different immune responses exerting varying effects on tumor growth. Furthermore, inflammatory mediators are closely involved in tumor initiation, local immune reactions, and other aspects of tumor biology. In research on various advanced malignancies, certain inflammatory biomarkers measured in peripheral blood have been found to predict treatment outcomes, highlighting their potential as prognostic tools [9-10] .For example, in the treatment of patients with metastatic nasopharyngeal carcinoma, an elevated ratio of peripheral blood lymphocytes to monocytes has been associated with the prognosis of these patients [11-12] .During the treatment of triple-negative breast cancer (TNBC), it has been observed that peripheral CD4+ T lymphocyte levels can serve as predictive biomarkers for patient prognosis following chemotherapy. Patients with higher peripheral CD4+ T cell counts tend to experience longer progression-free survival (PFS) and overall survival (OS). This finding highlights the important role of immune status in influencing treatment outcomes and may help guide more personalized therapeutic strategies for TNBC patients [13] .In patients with non-small cell lung cancer (NSCLC) undergoing neoadjuvant chemo-immunotherapy, studies have shown that those who achieve major pathologic response (MPR) tend to have significantly lower neutrophil-to-lymphocyte ratio (NLR) compared to non-MPR patients [14] .In inflammatory breast cancer, survival analysis has demonstrated that patients with lower neutrophil-to-lymphocyte ratio (NLR) tend to have significantly higher 5-year disease-free survival (DFS) and overall survival (OS). However, for patients with locally advanced esophageal cancer undergoing neoadjuvant chemo-immunotherapy, the relationship between peripheral blood lymphocyte subsets, inflammatory markers, and both pathological and radiographic responses remains unclear. The associations among these parameters warrant further investigation.This study primarily aims to analyze the correlation between peripheral blood lymphocyte parameters, inflammatory markers, and the pathological and radiographic responses in patients with locally advanced esophageal cancer receiving neoadjuvant chemo-immunotherapy. The goal is to identify potential predictive biomarkers of treatment efficacy, which could facilitate clinical assessment of response, guide treatment decisions, and promote the integration of neoadjuvant chemo-immunotherapy into routine clinical practice for managing locally advanced esophageal cancer. Data & Methodology 1. Research object This retrospective study collected comprehensive clinical data from a total of 100 patients with locally advanced esophageal cancer who underwent neoadjuvant chemo-immunotherapy at the Thoracic Surgery Department of The First Affiliated Hospital of Chongqing Medical University, spanning from September 2020 to December 2024. The collected data include patient demographics such as age, gender, and smoking status; as well as tumor-related information, including imaging data from CT scans, tumor size, lymph node metastasis status, histopathological type, clinical staging, routine blood tests, and lymphocyte counts. The treatment regimens used in all cases were based on platinum compounds and paclitaxel, combined with PD-L1 inhibitors. 2. Inclusion Criteria The preoperative biopsy pathology diagnosis confirms esophageal squamous cell carcinoma. (2) The clinical stage prior to treatment is either IIB or III, with measurable lesions present. (3) No prior anti-tumor treatments have been administered before this therapy. (4) All examinations and treatments are completed at The First Affiliated Hospital of Chongqing Medical University, with available peripheral blood lymphocyte data. (5) The treatment regimen consists of platinum-based and paclitaxel-based chemotherapy combined with a PD-L1 inhibitor, and the patient has undergone surgery at The First Affiliated Hospital of Chongqing Medical University. 3. Exclusion Criteria (1) Patients with failure of major organs such as the heart, liver, or kidneys; (2) Patients who have not received regular treatment; (3) Patients with hematologic or immune system diseases, or those with a history of prior immunotherapy; (4) Patients with incomplete clinical, pathological, or imaging data; (5) Patients with recent infectious diseases or similar conditions. This study utilized data retrieved from medical records, including age, gender, smoking history, histopathological characteristics, disease staging, use of PD-L1 inhibitors, and comorbidities. The treatment regimen was based on platinum-based chemotherapy (cisplatin 75 mg/m² on day 1) combined with albumin-bound paclitaxel (200 mg/m² on day 1) and combined with PD-L1 inhibitors. The immunotherapy agents included camrelizumab, tislelizumab, and pembrolizumab.According to RECIST version 1.1 criteria, patients achieving complete remission (CR) or partial remission (PR) were classified as responders, while those with stable disease (SD) or progressive disease (PD) were considered non-responders. The pathological response was evaluated to determine whether it achieved a pathologic complete response (PCR), dividing patients into a PCR group (responders) and a No-PCR group (non-responders) [15] .Patient samples were collected within 24 hours prior to the start of the first treatment cycle. Sterile venipuncture was performed to obtain fasting blood samples (> 200 μL), which were then immediately transported to the laboratory in vacutainer tubes at room temperature. The samples were processed within 24 hours of collection. 4. Statistical analysis All analyses in this study were conducted using R software version 4.0.3. Categorical data were summarized using numbers and percentages, with differences between groups assessed by the Chi-square test or Fisher’s exact test. Continuous variables were analyzed using Student’s t-test or one-way analysis of variance (ANOVA). The predictive value of various indicators for short-term efficacy of neoadjuvant therapy was evaluated through receiver operating characteristic (ROC) curves. Both univariate and multivariate analyses were performed using binary logistic regression. The significance level was set at α=0.05. Results Patient characteristics A retrospective cohort study included 100 patients with stage IIB or III esophageal squamous cell carcinoma who received platinum and taxane-based neoadjuvant chemotherapy combined with PD-L1 inhibitors at the Department of Thoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, between September 2020 and December 2024. The complete inclusion and exclusion criteria are as previously described. The average age was 64.08 years, with 87 males and 13 females. Smoking history was present in 51 patients, while 49 patients were non-smokers. All 100 patients were classified as stage III. The clinical and pathological characteristics of the enrolled patients are presented in Table 1. The postoperative pathological PCR group comprised 40 patients (40%), while the No-PCR group included 60 patients (60%). Using Fisher’s exact test, no significant differences were observed between the two groups in variables such as smoking history, age, alcohol consumption, height, weight, hypertension, clinical staging, absolute CD4+ T cell counts, diabetes, and gender (all P > 0.05).Significant differences were found between the groups in the absolute counts of total CD4+ T cells, CD4/CD8 ratio, neutrophil-to-lymphocyte ratio (NLR), and B lymphocyte counts (p < 0.05).Regarding the imaging-based cohort, patients were divided based on response after two cycles of neoadjuvant chemotherapy combined with immunotherapy: 46 patients achieved complete or partial response (CR/PR), and 54 patients had progressive disease or stable disease (PD/SD). Fisher’s exact test showed no significant differences between these groups in variables such as smoking history, age, alcohol consumption, height, weight, hypertension, clinical stage, absolute CD4+ T cell counts, CD4/CD8 ratio, NLR, B lymphocyte counts, diabetes, and gender (all P > 0.05). The only significant difference observed was in natural killer (NK) cell counts (p < 0.05). Correlation analysis between peripheral blood observation indexes and treatment response Based on the response to platinum plus paclitaxel combined with immunotherapy in patients with advanced esophageal cancer, patients were divided into two groups. Univariate analysis revealed that variables such as body weight, BMI, absolute CD4+ T cell count, CD4/CD8 ratio, NLR, double-negative T cell count, B lymphocyte count, and NKT cell count were significantly associated with the pathological PCR rate, with differences reaching statistical significance (P < 0.05). Refer to Table 3 for detailed results.In the imaging-based evaluation, no variables demonstrated a significant correlation with radiological response; all differences were statistically insignificant (P > 0.05), as shown in Table 4.Parameters with P < 0.05 from the pathological response analysis were further included in a multivariate logistic regression model. The results indicated that the CD4/CD8 ratio (odds ratio: 1.97, 95% confidence interval: 1.06–3.67, P = 0.032) and NLR (odds ratio: 0.57, 95% confidence interval: 0.37–0.88, P = 0.011) are independent predictors of pathological complete response (PCR). Refer to Table 5 for comprehensive details. ROC curves reveal the predictive value of CD4./CD8 and NLR for PCR ROC curve analysis of NLR and CD4+/CD8+ in predicting pathological complete response (pCR) after neoadjuvant chemotherapy combined with immunotherapy in patients with advanced esophageal cancer (see Figure 1). The area under the ROC curve (AUC) and the optimal cutoff points for NLR and CD4+/CD8+ were as follows: 0.692 (95% CI: 0.586–0.798) at a cutoff of 3.66, and 0.695 (95% CI: 0.591–0.799) at a cutoff of 1.72. The sensitivities were 87.5% and 90.0%, respectively, while the specificities were 60.0% and 58.3%, respectively (see Table 6). Discussion Currently, chemoradiotherapy combined with immunotherapy has gradually become the main treatment regimen for neoadjuvant therapy in patients with locally advanced esophageal cancer. However, due to tumor heterogeneity and individual differences among patients, there are variable responses to neoadjuvant treatment in some esophageal cancer cases. Therefore, it is necessary to develop methods for identifying potential responders to achieve precision medicine. Although some biomarkers have been identified that can potentially predict the effectiveness of neoadjuvant therapy in patients with esophageal squamous cell carcinoma, there remains a pressing need to discover more novel, reliable predictive factors to select patients most likely to benefit from such treatments [16] .Previous clinical trials have demonstrated that neoadjuvant chemotherapy combined with immunotherapy is safe, feasible, and associated with high R0 resection rates in patients with resectable, locally advanced esophageal cancer [17-19] .Several studies have also indicated that the addition of immunotherapy drugs to chemotherapy can significantly improve patient overall survival (OS) and progression-free survival (PFS) [20] .In this study, all patients received a neoadjuvant chemotherapy combined with immunotherapy regimen. The pathological complete response (PCR) rate was 40.0% (40/100), and the radiographic response rate was 46.0% (46/100), indicating favorable therapeutic outcomes. In this retrospective analysis, as of March 1, 2025, the patients exhibited longer survival durations, with only a minimal number of deaths and recurrences during follow-up, which did not reach statistical significance.This study analyzed the relationships between CD4+/CD8+ ratios, neutrophil-to-lymphocyte ratio (NLR), and PCR. Multivariate logistic regression analysis revealed that CD4+/CD8+ ratios and NLR were independently associated with pathological response. Specifically, the PCR group showed significantly higher CD4+/CD8+ ratios compared to the non-PCR group, while the NLR was notably lower in the PCR group than in the non-PCR group. These findings suggest that peripheral blood clinical parameters are correlated with the therapeutic efficacy of combined neoadjuvant chemoradiotherapy and immunotherapy in esophageal cancer. Moreover, ROC curve analysis validated the value of peripheral CD4+/CD8+ ratios and NLR in predicting treatment response in esophageal cancer patients.In this study, changes in peripheral blood parameters during treatment were not analyzed. One reason is that some patients experienced varying degrees of myelosuppression during therapy; clinical management tailored to individual patient conditions may have influenced these parameters, reducing data reliability. Additionally, collecting immunological indicators prior to treatment can better reflect patients’ baseline immune status and the impact of immunotherapy. Previous studies have shown that increases in CD4+ and CD8+ T cells, as well as changes observed through peripheral blood routine tests, are related to immune activity and inflammatory status, but these do not necessarily capture the specific inflammatory and immune conditions of the patients at the time of treatment [21] .Therefore, the results of this study suggest that pre-treatment biomarkers such as the CD4+/CD8+ ratio and NLR can be utilized to predict the therapeutic efficacy of neoadjuvant chemoradiotherapy combined with immunotherapy in patients with locally advanced esophageal cancer. However, further research is necessary to establish definitive optimal cutoff values for CD4+/CD8+ ratios and NLR, and to validate their predictive value in larger, prospective studies. In recent years, studies have indicated that the immune status and inflammatory responses of cancer patients are significantly associated with tumor initiation, progression, and metastasis. Immune cells within the tumor microenvironment play a crucial role in tumor recognition and immune-mediated attack, actively participating in mechanisms of tumor immune evasion [22] .In cancer treatment, combining chemotherapy with immunotherapy has shown promise by stimulating tumor cells to produce new tumor antigens, thereby enhancing the immune response. For example, chemotherapy primarily aims to kill tumor cells, and studies suggest that some drugs may also exert their effects by altering the immunophenotype of tumor cells, which increases the susceptibility of these cells to immune-mediated killing.Immune cells are classified based on various surface markers and phenotypes, including CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and NKT cells. Among these, CD4+ T cells can directly lyse tumor cells and also play a helper role by supporting the activation of cytotoxic CD8+ T cells and other immune effector cells, thereby further contributing to tumor eradication [23] .Certainly, the development and progression of tumors are not solely influenced by immune cells; inflammatory responses within the patient’s body also play a significant role. For instance, neutrophils may contribute by promoting the circulation of vascular endothelial growth factor (VEGF), thereby facilitating angiogenesis within the tumor and further supporting tumor growth and advancement [24] .From this, it is evident that immune responses and inflammatory reactions play crucial roles in the initiation and progression of tumors. The complex relationship among these factors warrants further investigation. Additionally, the association between these biomarkers and treatment outcomes remains an important area for future research. Currently, reliable predictive factors for esophageal cancer treatment efficacy are lacking.In this study, peripheral blood lymphocyte subsets and the neutrophil-to-lymphocyte ratio (NLR) were selected as observational indicators. These markers facilitate clinicians in selecting the most appropriate subsequent treatment strategies for patients. Although previous studies have suggested that baseline levels of certain proteins may be associated with overall survival (OS) and progression-free survival (PFS) in esophageal cancer patients undergoing treatment, the correlation between peripheral blood T lymphocyte subsets, inflammatory markers, and the short-term efficacy of neoadjuvant chemoradiotherapy combined with immunotherapy remains unclear.Furthermore, existing research indicates that lymphocytes such as CD4+ and CD8+ T cells, along with neutrophils, play significant roles in anti-tumor immunity. This underscores the importance of exploring the relationship between pre-treatment peripheral blood lymphocyte populations, neutrophil levels, and tumor response to therapy [25] .Here, our findings demonstrate that, compared to non-responders, responders (defined by pathological complete response and imaging-based CR/PR) exhibit a significantly higher CD4+/CD8+ T cell ratio and a markedly lower neutrophil-to-lymphocyte ratio (NLR).To date, the use of PD-L1-targeted therapies in patients with locally advanced esophageal cancer has become quite common, yielding encouraging results and improved patient outcomes [26] .PD-L1 plays a crucial role in tumor immune evasion by participating in the regulation of the body’s immune balance and immune tolerance. Studies have shown that during the immune response where T cells recognize and attack tumor cells, PD-L1 expressed on tumor cells can specifically bind to receptors on T cells. This interaction alters immune function and exerts negative regulatory effects, potentially inhibiting T cell activation and even preventing the lysis of tumor cells. As a result, the tumor can evade destruction by the immune system [27-30] .Among immune cells, CD4+ T cells primarily function as helper cells. During the immune response, they recognize antigens and activate CD8+ T cells, which then begin exerting cytotoxic effects. Additionally, CD4+ T cells play a synergistic role in enhancing the immune response by coordinating the activity of various immune cells and cytokines, thereby amplifying the overall immune-mediated attack against pathogens or abnormal cells [31] .This mechanism can further direct CD8+ T cells into the tumor stroma, thereby enhancing their cytotoxic effects. As indicated above, tumor cells may evade immune detection and destruction, leading to immune escape. Consequently, this allows the tumor to continue evolving and progressing without being effectively controlled by the immune system [32-33] .We considered whether modifying this negative regulation could enhance T cell function, thereby restoring the immune cells’ ability to effectively target and kill tumor cells [34] .Therefore, immune-related drugs are combined with chemotherapy to enhance treatment efficacy. For example, agents such as pembrolizumab, camrelizumab, and nivolumab have demonstrated favorable therapeutic outcomes. Of course, the mechanisms of the body’s immune response are influenced not only by tumor cell PD-L1 receptor expression but also by the patient’s own inflammatory reactions. Neutrophils, for instance, may promote tumor initiation and progression through the secretion of inflammatory cytokines [35] .Therefore, selecting relevant biomarkers to predict and improve treatment accuracy is of great importance. Due to the limitations associated with tissue sampling, we chose to study peripheral blood lymphocytes such as CD4+ T cells, CD8+ T cells, as well as neutrophils. Additionally, peripheral blood testing is cost-effective and can be routinely performed in patients undergoing treatment.In this study, we analyzed the relationships between pre-treatment peripheral blood CD4+/CD8+ T cell ratios and neutrophil-to-lymphocyte ratio (NLR) with treatment response, and found a certain correlation with histopathological response to therapy. These findings suggest that these biomarkers have the potential to serve as predictive indicators for the efficacy of neoadjuvant chemotherapy combined with immunotherapy in clinical practice. However, this study has certain limitations. First, the sample size was relatively small. Although preliminary conclusions were drawn, further research is necessary to explore and validate these findings. This was a single-center study with a limited number of participants. To confirm the results, large-scale, multicenter clinical studies are required. Additionally, we were unable to analyze the dynamic changes of lymphocytes during treatment and their relationship with therapeutic efficacy.Future prospective studies should be conducted to verify the correlation between peripheral blood inflammatory and immune markers and the efficacy of neoadjuvant chemotherapy combined with immunotherapy in patients with locally advanced esophageal cancer.In summary, advances in modern medicine and immunotherapy have enhanced our expectations for treatment outcomes. We anticipate that more research will further validate the use of peripheral blood CD4+/CD8+ T cells and NLR as effective predictive biomarkers for treatment response. Declarations Ethical Approval The research involving human participants was reviewed and approved by the Institutional Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. All experiments were conducted in accordance with relevant guidelines and regulations. As this was a retrospective, non-interventional study, written informed consent was not required from participants under national legislation and institutional requirements. The exemption from informed consent for this study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University.The ethics approval number is 2024-608-01 Competing interests The authors declare no competing interests. Funding This study was supported by the Research Fund of the First Affiliated Hospital of Chongqing Medical University. Author Contribution M-J.S.J-M.Y: Funding acquisition, Investigation, Writing – original draft, Data curation, Formal analysis, Writing – review & editing. 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Predictive value of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in non-small cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis Tables Tables 1 to 6 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7114130","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":486951043,"identity":"0fc8dbc1-b010-42a7-a0a2-a874ddc0c0f4","order_by":0,"name":"Mingjian Sheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIie3RMQrCMBSA4UAgUzTrCxbdnAOCk+BVGoROCrp16BBR2kG7ewzHjpVCpujs2N5ANwUHLY5KWzeHfFOG/CQvQciy/hDpHZbF9RFQxlaH3PWD+qQNOBtwpR2+0xORG12fdIF40FJ4JNJpnxdr3OBina0AnhDKlSG+VASxaONWJ44RYmEcynCszzJxEJjjvjpBU+ECKU85eWdpCBIwq09SSjB9zTKcyxA3SMCTqhW+E9QsoVmGwWhaPjK4r0XtLL1oGd0vfjAuv/J684Mui+Lq5AP9bbtlWZb11RNG0klvZx4VNQAAAABJRU5ErkJggg==","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Mingjian","middleName":"","lastName":"Sheng","suffix":""},{"id":486951046,"identity":"bed0dac2-7fdc-4c9c-8278-a3e5d53dff80","order_by":1,"name":"Yang Xiang","email":"","orcid":"","institution":"Qianjiang Hospital Affiliated to Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Xiang","suffix":""},{"id":486951049,"identity":"ed5388a5-d55a-42f8-b550-4b3173a55467","order_by":2,"name":"Jiming Yang","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University, Chongqing, China","correspondingAuthor":false,"prefix":"","firstName":"Jiming","middleName":"","lastName":"Yang","suffix":""},{"id":486951050,"identity":"c2503a8b-3b48-41d8-b6cd-3da9835450ed","order_by":3,"name":"Li Chen","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Chen","suffix":""},{"id":486951053,"identity":"c3fc8112-f824-40ec-a53c-3ded36a61070","order_by":4,"name":"Tianyang Zeng","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tianyang","middleName":"","lastName":"Zeng","suffix":""}],"badges":[],"createdAt":"2025-07-13 15:08:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7114130/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7114130/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87364643,"identity":"5109fbdf-afc0-4093-bc1c-bad45da54e1a","added_by":"auto","created_at":"2025-07-23 06:19:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":111101,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7114130/v1/7add93de19b72272a2faa2b2.png"},{"id":89729737,"identity":"e339802a-ae15-4809-ab8a-a1c456b7d803","added_by":"auto","created_at":"2025-08-23 13:16:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":503575,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7114130/v1/d8a00b5d-f3f8-45c0-9d6e-efdc74a21897.pdf"},{"id":87364646,"identity":"53bb5821-83e6-4e5e-9d90-1de5508594ae","added_by":"auto","created_at":"2025-07-23 06:19:25","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":70778,"visible":true,"origin":"","legend":"","description":"","filename":"table.docx","url":"https://assets-eu.researchsquare.com/files/rs-7114130/v1/813923763ee6062182fe1cd4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Predictive Value of Peripheral Blood CD4+/CD8+ Ratio and NLR for Short-term Efficacy of Neoadjuvant Chemotherapy Combined with Immunotherapy in Locally Advanced Esophageal Cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCurrently, esophageal cancer is one of the most common malignant tumors worldwide. Approximately 78% of esophageal cancer cases occur in Asia, with China accounting for 49% of the cases\u003csup\u003e[3-4]\u003c/sup\u003e.China is a high-incidence region for esophageal cancer. Although the incidence and mortality rates have generally declined with economic development and improved living standards, certain areas still see esophageal cancer posing a significant threat to public health. These regional disparities may be related to economic factors and dietary habits in different parts of China. The pathological types of esophageal cancer include squamous cell carcinoma, adenocarcinoma, and basal cell carcinoma, among which squamous cell carcinoma is the most common type of esophageal malignant tumor in China\u003csup\u003e[5]\u003c/sup\u003e.With advancements in modern biomedical technology, the survival rates of cancer patients have improved, along with better prognoses and quality of life. The treatment approach for esophageal cancer has evolved from traditional chemotherapy to neoadjuvant chemoradiotherapy, and now to combined immunotherapy, providing greater benefits to patients. Currently, preoperative neoadjuvant therapy, surgery, and postoperative chemoradiotherapy are the mainstays of esophageal cancer treatment. For some early-stage patients, endoscopic therapy may be an option, while those with locally advanced disease often undergo neoadjuvant therapy first, followed by an assessment to determine the suitability for surgery. According to the international staging system (AJCC 8th edition), neoadjuvant chemoradiotherapy is becoming increasingly common in patients with stage IIB or stage III esophageal cancer\u003csup\u003e[6]\u003c/sup\u003e.In recent years, neoadjuvant chemotherapy has significantly improved the overall survival of patients with locally advanced esophageal cancer. The current neoadjuvant chemotherapy regimens for these patients include combinations such as paclitaxel with platinum-based agents, cisplatin with fluorouracil or capecitabine, or tegafur-based therapies\u003csup\u003e[7]\u003c/sup\u003e.Currently, immunotherapy is increasingly being utilized in the treatment of esophageal cancer. The combination of pembrolizumab or nivolumab with chemotherapy has been approved by the European Medicines Agency as a first-line treatment for esophageal squamous cell carcinoma (ESCC) with high PD-L1 expression. Clinical studies have also confirmed that combining immunotherapy with chemotherapy offers greater therapeutic benefits compared to chemotherapy alone\u003csup\u003e[8]\u003c/sup\u003e.Patients who undergo neoadjuvant chemotherapy combined with immunotherapy have demonstrated improved survival outcomes. However, it is important to recognize that only a limited subset of esophageal cancer patients may benefit from this combined treatment approach. Therefore, identifying reliable biomarkers to distinguish responders from non-responders is crucial.\u003c/p\u003e\n\u003cp\u003ePrevious studies have shown that tumor-associated immune responses are closely linked to tumor development, progression, and patient prognosis. Currently, it is understood that cellular immunity plays a dominant role in the immune response against tumors, with different immune responses exerting varying effects on tumor growth. Furthermore, inflammatory mediators are closely involved in tumor initiation, local immune reactions, and other aspects of tumor biology. In research on various advanced malignancies, certain inflammatory biomarkers measured in peripheral blood have been found to predict treatment outcomes, highlighting their potential as prognostic tools\u003csup\u003e[9-10]\u003c/sup\u003e.For example, in the treatment of patients with metastatic nasopharyngeal carcinoma, an elevated ratio of peripheral blood lymphocytes to monocytes has been associated with the prognosis of these patients\u003csup\u003e[11-12]\u003c/sup\u003e.During the treatment of triple-negative breast cancer (TNBC), it has been observed that peripheral CD4+ T lymphocyte levels can serve as predictive biomarkers for patient prognosis following chemotherapy. Patients with higher peripheral CD4+ T cell counts tend to experience longer progression-free survival (PFS) and overall survival (OS). This finding highlights the important role of immune status in influencing treatment outcomes and may help guide more personalized therapeutic strategies for TNBC patients\u003csup\u003e[13]\u003c/sup\u003e.In patients with non-small cell lung cancer (NSCLC) undergoing neoadjuvant chemo-immunotherapy, studies have shown that those who achieve major pathologic response (MPR) tend to have significantly lower neutrophil-to-lymphocyte ratio (NLR) compared to non-MPR patients\u003csup\u003e[14]\u003c/sup\u003e.In inflammatory breast cancer, survival analysis has demonstrated that patients with lower neutrophil-to-lymphocyte ratio (NLR) tend to have significantly higher 5-year disease-free survival (DFS) and overall survival (OS). However, for patients with locally advanced esophageal cancer undergoing neoadjuvant chemo-immunotherapy, the relationship between peripheral blood lymphocyte subsets, inflammatory markers, and both pathological and radiographic responses remains unclear. The associations among these parameters warrant further investigation.This study primarily aims to analyze the correlation between peripheral blood lymphocyte parameters, inflammatory markers, and the pathological and radiographic responses in patients with locally advanced esophageal cancer receiving neoadjuvant chemo-immunotherapy. The goal is to identify potential predictive biomarkers of treatment efficacy, which could facilitate clinical assessment of response, guide treatment decisions, and promote the integration of neoadjuvant chemo-immunotherapy into routine clinical practice for managing locally advanced esophageal cancer.\u003c/p\u003e"},{"header":"Data \u0026 Methodology","content":"\u003cp\u003e1. Research object\u003c/p\u003e\n\u003cp\u003eThis retrospective study collected comprehensive clinical data from a total of 100 patients with locally advanced esophageal cancer who underwent neoadjuvant chemo-immunotherapy at the Thoracic Surgery Department of The First Affiliated Hospital of Chongqing Medical University, spanning from September 2020 to December 2024. The collected data include patient demographics such as age, gender, and smoking status; as well as tumor-related information, including imaging data from CT scans, tumor size, lymph node metastasis status, histopathological type, clinical staging, routine blood tests, and lymphocyte counts. The treatment regimens used in all cases were based on platinum compounds and paclitaxel, combined with PD-L1 inhibitors.\u003c/p\u003e\n\u003cp\u003e2. Inclusion Criteria\u003c/p\u003e\n\u003cp\u003eThe preoperative biopsy pathology diagnosis confirms esophageal squamous cell carcinoma.\u003c/p\u003e\n\u003cp\u003e(2) The clinical stage prior to treatment is either IIB or III, with measurable lesions present.\u003c/p\u003e\n\u003cp\u003e(3) No prior anti-tumor treatments have been administered before this therapy.\u003c/p\u003e\n\u003cp\u003e(4) All examinations and treatments are completed at The First Affiliated Hospital of Chongqing Medical University, with available peripheral blood lymphocyte data.\u003c/p\u003e\n\u003cp\u003e(5) The treatment regimen consists of platinum-based and paclitaxel-based chemotherapy combined with a PD-L1 inhibitor, and the patient has undergone surgery at The First Affiliated Hospital of Chongqing Medical University.\u003c/p\u003e\n\u003cp\u003e3. Exclusion Criteria\u003c/p\u003e\n\u003cp\u003e(1) Patients with failure of major organs such as the heart, liver, or kidneys;\u003c/p\u003e\n\u003cp\u003e(2) Patients who have not received regular treatment;\u003c/p\u003e\n\u003cp\u003e(3) Patients with hematologic or immune system diseases, or those with a history of prior immunotherapy;\u003c/p\u003e\n\u003cp\u003e(4) Patients with incomplete clinical, pathological, or imaging data;\u003c/p\u003e\n\u003cp\u003e(5) Patients with recent infectious diseases or similar conditions.\u003c/p\u003e\n\u003cp\u003eThis study utilized data retrieved from medical records, including age, gender, smoking history, histopathological characteristics, disease staging, use of PD-L1 inhibitors, and comorbidities. The treatment regimen was based on platinum-based chemotherapy (cisplatin 75 mg/m\u0026sup2; on day 1) combined with albumin-bound paclitaxel (200 mg/m\u0026sup2; on day 1) and combined with PD-L1 inhibitors. The immunotherapy agents included camrelizumab, tislelizumab, and pembrolizumab.According to RECIST version 1.1 criteria, patients achieving complete remission (CR) or partial remission (PR) were classified as responders, while those with stable disease (SD) or progressive disease (PD) were considered non-responders. The pathological response was evaluated to determine whether it achieved a pathologic complete response (PCR), dividing patients into a PCR group (responders) and a No-PCR group (non-responders)\u003csup\u003e[15]\u003c/sup\u003e.Patient samples were collected within 24 hours prior to the start of the first treatment cycle. Sterile venipuncture was performed to obtain fasting blood samples (\u0026gt; 200 \u0026mu;L), which were then immediately transported to the laboratory in vacutainer tubes at room temperature. The samples were processed within 24 hours of collection.\u003c/p\u003e\n\u003cp\u003e4. Statistical analysis\u003c/p\u003e\n\u003cp\u003eAll analyses in this study were conducted using R software version 4.0.3. Categorical data were summarized using numbers and percentages, with differences between groups assessed by the Chi-square test or Fisher\u0026rsquo;s exact test. Continuous variables were analyzed using Student\u0026rsquo;s t-test or one-way analysis of variance (ANOVA). The predictive value of various indicators for short-term efficacy of neoadjuvant therapy was evaluated through receiver operating characteristic (ROC) curves. Both univariate and multivariate analyses were performed using binary logistic regression. The significance level was set at \u0026alpha;=0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics\u003c/p\u003e\n\u003cp\u003eA retrospective cohort study included 100 patients with stage IIB or III esophageal squamous cell carcinoma who received platinum and taxane-based neoadjuvant chemotherapy combined with PD-L1 inhibitors at the Department of Thoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, between September 2020 and December 2024. The complete inclusion and exclusion criteria are as previously described. The average age was 64.08 years, with 87 males and 13 females. Smoking history was present in 51 patients, while 49 patients were non-smokers. All 100 patients were classified as stage III.\u003c/p\u003e\n\u003cp\u003eThe clinical and pathological characteristics of the enrolled patients are presented in Table 1. The postoperative pathological PCR group comprised 40 patients (40%), while the No-PCR group included 60 patients (60%). Using Fisher\u0026rsquo;s exact test, no significant differences were observed between the two groups in variables such as smoking history, age, alcohol consumption, height, weight, hypertension, clinical staging, absolute CD4+ T cell counts, diabetes, and gender (all P \u0026gt; 0.05).Significant differences were found between the groups in the absolute counts of total CD4+ T cells, CD4/CD8 ratio, neutrophil-to-lymphocyte ratio (NLR), and B lymphocyte counts (p \u0026lt; 0.05).Regarding the imaging-based cohort, patients were divided based on response after two cycles of neoadjuvant chemotherapy combined with immunotherapy: 46 patients achieved complete or partial response (CR/PR), and 54 patients had progressive disease or stable disease (PD/SD). Fisher\u0026rsquo;s exact test showed no significant differences between these groups in variables such as smoking history, age, alcohol consumption, height, weight, hypertension, clinical stage, absolute CD4+ T cell counts, CD4/CD8 ratio, NLR, B lymphocyte counts, diabetes, and gender (all P \u0026gt; 0.05). The only significant difference observed was in natural killer (NK) cell counts (p \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003eCorrelation analysis between peripheral blood observation indexes and treatment response\u003c/p\u003e\n\u003cp\u003eBased on the response to platinum plus paclitaxel combined with immunotherapy in patients with advanced esophageal cancer, patients were divided into two groups. Univariate analysis revealed that variables such as body weight, BMI, absolute CD4+ T cell count, CD4/CD8 ratio, NLR, double-negative T cell count, B lymphocyte count, and NKT cell count were significantly associated with the pathological PCR rate, with differences reaching statistical significance (P \u0026lt; 0.05). Refer to Table 3 for detailed results.In the imaging-based evaluation, no variables demonstrated a significant correlation with radiological response; all differences were statistically insignificant (P \u0026gt; 0.05), as shown in Table 4.Parameters with P \u0026lt; 0.05 from the pathological response analysis were further included in a multivariate logistic regression model. The results indicated that the CD4/CD8 ratio (odds ratio: 1.97, 95% confidence interval: 1.06\u0026ndash;3.67, P = 0.032) and NLR (odds ratio: 0.57, 95% confidence interval: 0.37\u0026ndash;0.88, P = 0.011) are independent predictors of pathological complete response (PCR). Refer to Table 5 for comprehensive details.\u003c/p\u003e\n\u003cp\u003eROC curves reveal the predictive value of CD4./CD8 and NLR for PCR\u003c/p\u003e\n\u003cp\u003eROC curve analysis of NLR and CD4+/CD8+ in predicting pathological complete response (pCR) after neoadjuvant chemotherapy combined with immunotherapy in patients with advanced esophageal cancer (see Figure 1). The area under the ROC curve (AUC) and the optimal cutoff points for NLR and CD4+/CD8+ were as follows: 0.692 (95% CI: 0.586\u0026ndash;0.798) at a cutoff of 3.66, and 0.695 (95% CI: 0.591\u0026ndash;0.799) at a cutoff of 1.72. The sensitivities were 87.5% and 90.0%, respectively, while the specificities were 60.0% and 58.3%, respectively (see Table 6).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCurrently, chemoradiotherapy combined with immunotherapy has gradually become the main treatment regimen for neoadjuvant therapy in patients with locally advanced esophageal cancer. However, due to tumor heterogeneity and individual differences among patients, there are variable responses to neoadjuvant treatment in some esophageal cancer cases. Therefore, it is necessary to develop methods for identifying potential responders to achieve precision medicine. Although some biomarkers have been identified that can potentially predict the effectiveness of neoadjuvant therapy in patients with esophageal squamous cell carcinoma, there remains a pressing need to discover more novel, reliable predictive factors to select patients most likely to benefit from such treatments\u003csup\u003e[16]\u003c/sup\u003e.Previous clinical trials have demonstrated that neoadjuvant chemotherapy combined with immunotherapy is safe, feasible, and associated with high R0 resection rates in patients with resectable, locally advanced esophageal cancer\u003csup\u003e[17-19]\u003c/sup\u003e.Several studies have also indicated that the addition of immunotherapy drugs to chemotherapy can significantly improve patient overall survival (OS) and progression-free survival (PFS)\u003csup\u003e[20]\u003c/sup\u003e.In this study, all patients received a neoadjuvant chemotherapy combined with immunotherapy regimen. The pathological complete response (PCR) rate was 40.0% (40/100), and the radiographic response rate was 46.0% (46/100), indicating favorable therapeutic outcomes. In this retrospective analysis, as of March 1, 2025, the patients exhibited longer survival durations, with only a minimal number of deaths and recurrences during follow-up, which did not reach statistical significance.This study analyzed the relationships between CD4+/CD8+ ratios, neutrophil-to-lymphocyte ratio (NLR), and PCR. Multivariate logistic regression analysis revealed that CD4+/CD8+ ratios and NLR were independently associated with pathological response. Specifically, the PCR group showed significantly higher CD4+/CD8+ ratios compared to the non-PCR group, while the NLR was notably lower in the PCR group than in the non-PCR group. These findings suggest that peripheral blood clinical parameters are correlated with the therapeutic efficacy of combined neoadjuvant chemoradiotherapy and immunotherapy in esophageal cancer. Moreover, ROC curve analysis validated the value of peripheral CD4+/CD8+ ratios and NLR in predicting treatment response in esophageal cancer patients.In this study, changes in peripheral blood parameters during treatment were not analyzed. One reason is that some patients experienced varying degrees of myelosuppression during therapy; clinical management tailored to individual patient conditions may have influenced these parameters, reducing data reliability. Additionally, collecting immunological indicators prior to treatment can better reflect patients\u0026rsquo; baseline immune status and the impact of immunotherapy. Previous studies have shown that increases in CD4+ and CD8+ T cells, as well as changes observed through peripheral blood routine tests, are related to immune activity and inflammatory status, but these do not necessarily capture the specific inflammatory and immune conditions of the patients at the time of treatment\u003csup\u003e[21]\u003c/sup\u003e.Therefore, the results of this study suggest that pre-treatment biomarkers such as the CD4+/CD8+ ratio and NLR can be utilized to predict the therapeutic efficacy of neoadjuvant chemoradiotherapy combined with immunotherapy in patients with locally advanced esophageal cancer. However, further research is necessary to establish definitive optimal cutoff values for CD4+/CD8+ ratios and NLR, and to validate their predictive value in larger, prospective studies.\u003c/p\u003e\n\u003cp\u003eIn recent years, studies have indicated that the immune status and inflammatory responses of cancer patients are significantly associated with tumor initiation, progression, and metastasis. Immune cells within the tumor microenvironment play a crucial role in tumor recognition and immune-mediated attack, actively participating in mechanisms of tumor immune evasion\u003csup\u003e[22]\u003c/sup\u003e.In cancer treatment, combining chemotherapy with immunotherapy has shown promise by stimulating tumor cells to produce new tumor antigens, thereby enhancing the immune response. For example, chemotherapy primarily aims to kill tumor cells, and studies suggest that some drugs may also exert their effects by altering the immunophenotype of tumor cells, which increases the susceptibility of these cells to immune-mediated killing.Immune cells are classified based on various surface markers and phenotypes, including CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and NKT cells. Among these, CD4+ T cells can directly lyse tumor cells and also play a helper role by supporting the activation of cytotoxic CD8+ T cells and other immune effector cells, thereby further contributing to tumor eradication\u003csup\u003e[23]\u003c/sup\u003e.Certainly, the development and progression of tumors are not solely influenced by immune cells; inflammatory responses within the patient\u0026rsquo;s body also play a significant role. For instance, neutrophils may contribute by promoting the circulation of vascular endothelial growth factor (VEGF), thereby facilitating angiogenesis within the tumor and further supporting tumor growth and advancement\u003csup\u003e[24]\u003c/sup\u003e.From this, it is evident that immune responses and inflammatory reactions play crucial roles in the initiation and progression of tumors. The complex relationship among these factors warrants further investigation. Additionally, the association between these biomarkers and treatment outcomes remains an important area for future research. Currently, reliable predictive factors for esophageal cancer treatment efficacy are lacking.In this study, peripheral blood lymphocyte subsets and the neutrophil-to-lymphocyte ratio (NLR) were selected as observational indicators. These markers facilitate clinicians in selecting the most appropriate subsequent treatment strategies for patients. Although previous studies have suggested that baseline levels of certain proteins may be associated with overall survival (OS) and progression-free survival (PFS) in esophageal cancer patients undergoing treatment, the correlation between peripheral blood T lymphocyte subsets, inflammatory markers, and the short-term efficacy of neoadjuvant chemoradiotherapy combined with immunotherapy remains unclear.Furthermore, existing research indicates that lymphocytes such as CD4+ and CD8+ T cells, along with neutrophils, play significant roles in anti-tumor immunity. This underscores the importance of exploring the relationship between pre-treatment peripheral blood lymphocyte populations, neutrophil levels, and tumor response to therapy\u003csup\u003e[25]\u003c/sup\u003e.Here, our findings demonstrate that, compared to non-responders, responders (defined by pathological complete response and imaging-based CR/PR) exhibit a significantly higher CD4+/CD8+ T cell ratio and a markedly lower neutrophil-to-lymphocyte ratio (NLR).To date, the use of PD-L1-targeted therapies in patients with locally advanced esophageal cancer has become quite common, yielding encouraging results and improved patient outcomes\u003csup\u003e[26]\u003c/sup\u003e.PD-L1 plays a crucial role in tumor immune evasion by participating in the regulation of the body\u0026rsquo;s immune balance and immune tolerance. Studies have shown that during the immune response where T cells recognize and attack tumor cells, PD-L1 expressed on tumor cells can specifically bind to receptors on T cells. This interaction alters immune function and exerts negative regulatory effects, potentially inhibiting T cell activation and even preventing the lysis of tumor cells. As a result, the tumor can evade destruction by the immune system\u003csup\u003e[27-30]\u003c/sup\u003e.Among immune cells, CD4+ T cells primarily function as helper cells. During the immune response, they recognize antigens and activate CD8+ T cells, which then begin exerting cytotoxic effects. Additionally, CD4+ T cells play a synergistic role in enhancing the immune response by coordinating the activity of various immune cells and cytokines, thereby amplifying the overall immune-mediated attack against pathogens or abnormal cells\u003csup\u003e[31]\u003c/sup\u003e.This mechanism can further direct CD8+ T cells into the tumor stroma, thereby enhancing their cytotoxic effects. As indicated above, tumor cells may evade immune detection and destruction, leading to immune escape. Consequently, this allows the tumor to continue evolving and progressing without being effectively controlled by the immune system\u003csup\u003e[32-33]\u003c/sup\u003e.We considered whether modifying this negative regulation could enhance T cell function, thereby restoring the immune cells\u0026rsquo; ability to effectively target and kill tumor cells\u003csup\u003e[34]\u003c/sup\u003e.Therefore, immune-related drugs are combined with chemotherapy to enhance treatment efficacy. For example, agents such as pembrolizumab, camrelizumab, and nivolumab have demonstrated favorable therapeutic outcomes. Of course, the mechanisms of the body\u0026rsquo;s immune response are influenced not only by tumor cell PD-L1 receptor expression but also by the patient\u0026rsquo;s own inflammatory reactions. Neutrophils, for instance, may promote tumor initiation and progression through the secretion of inflammatory cytokines\u003csup\u003e[35]\u003c/sup\u003e.Therefore, selecting relevant biomarkers to predict and improve treatment accuracy is of great importance. Due to the limitations associated with tissue sampling, we chose to study peripheral blood lymphocytes such as CD4+ T cells, CD8+ T cells, as well as neutrophils. Additionally, peripheral blood testing is cost-effective and can be routinely performed in patients undergoing treatment.In this study, we analyzed the relationships between pre-treatment peripheral blood CD4+/CD8+ T cell ratios and neutrophil-to-lymphocyte ratio (NLR) with treatment response, and found a certain correlation with histopathological response to therapy. These findings suggest that these biomarkers have the potential to serve as predictive indicators for the efficacy of neoadjuvant chemotherapy combined with immunotherapy in clinical practice.\u003c/p\u003e\n\u003cp\u003eHowever, this study has certain limitations. First, the sample size was relatively small. Although preliminary conclusions were drawn, further research is necessary to explore and validate these findings. This was a single-center study with a limited number of participants. To confirm the results, large-scale, multicenter clinical studies are required. Additionally, we were unable to analyze the dynamic changes of lymphocytes during treatment and their relationship with therapeutic efficacy.Future prospective studies should be conducted to verify the correlation between peripheral blood inflammatory and immune markers and the efficacy of neoadjuvant chemotherapy combined with immunotherapy in patients with locally advanced esophageal cancer.In summary, advances in modern medicine and immunotherapy have enhanced our expectations for treatment outcomes. We anticipate that more research will further validate the use of peripheral blood CD4+/CD8+ T cells and NLR as effective predictive biomarkers for treatment response.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthical Approval\u003c/h2\u003e\n\u003cp\u003eThe research involving human participants was reviewed and approved by the Institutional Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. All experiments were conducted in accordance with relevant guidelines and regulations. As this was a retrospective, non-interventional study, written informed consent was not required from participants under national legislation and institutional requirements. The exemption from informed consent for this study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University.The ethics approval number is 2024-608-01\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study was supported by the Research Fund of the First Affiliated Hospital of Chongqing Medical University.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eM-J.S.J-M.Y: Funding acquisition, Investigation, Writing \u0026ndash; original draft, Data curation, Formal analysis, Writing \u0026ndash; review \u0026amp; editing. Y.X.M-J.S: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing \u0026ndash; review \u0026amp; editing, Writing \u0026ndash; original draft. T-Y.Z.L.C: Conceptualization, Funding acquisition, Supervision, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eThe authors thank all the patients who participated in this study.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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This study aims to investigate the predictive value of the peripheral blood CD4+/CD8+ ratio and NLR in assessing the short-term efficacy of neoadjuvant chemotherapy combined with immunotherapy in patients with locally advanced esophageal cancer.In this research, we compared the differences in lymphocyte subpopulations and NLR between patients achieving pathological complete response (pCR) and those who did not, as well as between those with radiographic remission (CR/PR) and those without (PD/SD) prior to treatment. The analysis revealed that patients with a high CD4+/CD8+ ratio and a low NLR were more likely to achieve pCR (P \u0026lt; 0.05). However, these differences were not statistically significant when considering radiographic response (P \u0026gt; 0.05).These findings suggest that these biomarkers could be useful in predicting the effectiveness of the treatment in esophageal cancer patients, facilitating more precise and personalized therapeutic strategies.\u003c/p\u003e","manuscriptTitle":"The Predictive Value of Peripheral Blood CD4+/CD8+ Ratio and NLR for Short-term Efficacy of Neoadjuvant Chemotherapy Combined with Immunotherapy in Locally Advanced Esophageal Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 06:19:20","doi":"10.21203/rs.3.rs-7114130/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d07c940c-b9c8-4740-99b9-9410ffef9772","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-23T13:08:46+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-23 06:19:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7114130","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7114130","identity":"rs-7114130","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}