Prognostic Value of Tertiary Lymphoid Structures in Cancer - A Systematic Review and Meta-Analysis

Background: Some studies have found that immune cell spatial structures, also known as tertiary lymphoid structures (TLSs), may have prognostic value in cancer. However, these studies all had insufficient sample sizes and inconsistent conclusions. To overcome these problems and draw conclusions, a systematic review and meta-analysis was conducted to determine the prognostic impact of TLSs in cancer. Methods: : PubMed, Web of Science, and Embase databases were searched to identify eligible articles published before April 2021. Two authors assessed each record, ensuring that the PICOS framework was met, and risk of bias on the study level was assessed using the Cochrane Bias Risk Assessment Tool. We then performed a meta-analysis using Review Manager 5.3 program to obtain a comprehensive estimate of the prognostic role of TLSs. Results: : In total, 28 studies were included in our analysis. We found that in comparison to cancer patients with low TLSs levels, those with high TLSs levels had a better overall survival (OS, hazard ratio [HR]: 0.48, 95% confidence interval [CI]: 0.40-0.57, p<0.00001) and disease-free survival (DFS, HR: 0.52, 95% CI: 0.42-0.63, p<0.00001). Surprisingly, after receiving immune checkpoint inhibitors (ICIs) therapy, cancer patients with high TLSs levels also had a better OS (HR, 0.28; 95% CI, 0.16-0.48; p<0.00001). Furthermore, our subgroup analysis showed that the density of DC-Lamp+ dendritic cells (DCs) and CD20+ B cells in TLSs represented better clinical outcomes. Conclusion: To the best of our knowledge, this study is the first meta-analysis to show the significant prognostic value of TLSs in cancer, to date. Moreover, TLSs are expected to be a potential marker for predicting anti-tumor immune response, which may help clinicians to select patients with cancer who are sensitive to immunotherapy. In addition to their concentration, TLSs components also had strong prognostic value. In particular, the study may provide a novel therapeutic target for patients with cancer and provide a new theoretical basis for future research on tumor immunotherapy.