Adipose Tissue-Associated Lipid Serum Signatures Modulate Efficacy and Toxicity of CAR-T Cell Therapy in Lymphoid Malignancies

Adipose Tissue-Associated Lipid Serum Signatures Modulate Efficacy and Toxicity of CAR-T Cell Therapy in Lymphoid Malignancies | 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 Letter Adipose Tissue-Associated Lipid Serum Signatures Modulate Efficacy and Toxicity of CAR-T Cell Therapy in Lymphoid Malignancies David Cordas Dos Santos, Hannah Thurisch, Jingke Tu, Daniel Heilpern-Mallory, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7755612/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 host metabolic state is a key regulator of immune cell function and may influence outcomes of T-cell–based therapies. To investigate the role of adiposity in CAR-T cell therapy, we integrated computed tomography–based body composition analysis with targeted mass spectrometry of 158 longitudinal serum samples from 54 patients with relapsed B-cell lymphoma. We identify distinct adipose tissue–associated lipid classes linked to survival and the development of cytokine release syndrome (CRS), with visceral adiposity–dependent dynamics during therapy. Among these, associations between acylcarnitines and phosphatidylethanolamines with CRS were independently validated in a separate cohort of 17 patients with B-cell lymphoma and myeloma. In parallel, single-cell RNA sequencing of murine bone marrow immune cells in vitro cultured under obesity-mimicking conditions revealed a pro-inflammatory transcriptional program in key immune cell subsets, implicating adipose-derived metabolic signals in immune modulation. These findings highlight a link between host metabolic and body compositional states and CAR-T function and support the integration of metabolic profiling into precision immunotherapy. Health sciences/Oncology/Cancer/Haematological cancer Health sciences/Oncology/Cancer/Cancer therapy/Cancer immunotherapy Health sciences/Medical research/Translational research Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity Adipose Tissue Body Composition Chimeric Antigen Receptor Lipidomics Serum Metabolomics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations Yes there is potential Competing Interest. D.M.C.D.S. Regeneron: Research funding. Pending provisional US patent filed in 2024 (U.S. Patent Application No. 63/716,000). K.R. Kite/Gilead: Research Funding, Consultancy, Honoraria and travel support; Novartis: Honoraria; BMS/Celgene: Consultancy, Honoraria; Pierre-Fabre: Travel support. CSL Behring: Consultancy. M.S. Education Grants: BMS, Gilead/Kite, Johnson and Johnson, Novartis. Honoraria: Gilead/Kite. Advisory Boards: Interius, Takeda, Gilead/Kite, Novartis, BMS. S.T. Consulting Fees: Johnson & Johnson, Pfizer, Sanofi, Menarini Stemline, Oncopeptides, Bristol-Myers-Squibb, Glaxo-Smith-Kline, Takeda, Kyowa Kirin. Payment for Expert Testimony: Johnson & Johnson, Pfizer, Sanofi, Menarini Stemline, Oncopeptides, Bristol-Myers-Squibb, Glaxo-Smith-Kline, Takeda, Kyowa Kirin. Travel Support: Johnson & Johnson, Pfizer, Sanofi, Menarini Stemline, Oncopeptides, Bristol-Myers-Squibb, Glaxo-Smith-Kline, Takeda, Kyowa Kirin. The remaining authors have nothing to declare. None of the mentioned conflicts of interest were related to the financing of the content of this manuscript. Supplementary Files NatMetCARTMetabolomicsReportingSummary250927.pdf Nature Reporting Summary NatMetCARTMetabolomicsSupplFiles250930.pdf Supplementary Files 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-7755612","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Letter","associatedPublications":[],"authors":[{"id":530721158,"identity":"89c112a1-c5be-4e11-b222-60abe7c4000b","order_by":0,"name":"David Cordas Dos 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Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Vaeth","suffix":""},{"id":530721166,"identity":"e8cad41c-27a9-445e-a309-945259cc797b","order_by":8,"name":"Oganesian Sabine","email":"","orcid":"","institution":"LMU Munich","correspondingAuthor":false,"prefix":"","firstName":"Oganesian","middleName":"","lastName":"Sabine","suffix":""},{"id":530721167,"identity":"4d0b1fbd-28c4-46aa-b75d-af93c16b0d4b","order_by":9,"name":"Adriano Carboneiro","email":"","orcid":"","institution":"LMU University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Adriano","middleName":"","lastName":"Carboneiro","suffix":""},{"id":530721168,"identity":"ccdb6a27-a332-4444-ab7a-dd9295890ab5","order_by":10,"name":"Ludovica Vona","email":"","orcid":"","institution":"LMU University 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tobias","middleName":"","lastName":"Tix","suffix":""},{"id":530721172,"identity":"487f07ec-e8b0-463f-a9e0-00d51acc0680","order_by":14,"name":"Michael von Bergwelt-Baildon","email":"","orcid":"","institution":"LMU University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"von Bergwelt-Baildon","suffix":""},{"id":530721173,"identity":"0996f810-d759-4224-9ec2-8f5056c80933","order_by":15,"name":"Kai Rejeski","email":"","orcid":"","institution":"LMU University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kai","middleName":"","lastName":"Rejeski","suffix":""},{"id":530721174,"identity":"76ef9456-0b18-4d30-8a44-2454b1ac5cee","order_by":16,"name":"Marion Subklewe","email":"","orcid":"","institution":"LMU University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Marion","middleName":"","lastName":"Subklewe","suffix":""},{"id":530721175,"identity":"2dee9b8f-ec12-4c3e-923f-5e86ba1d155b","order_by":17,"name":"Sebastian Theurich","email":"","orcid":"https://orcid.org/0000-0001-5706-8258","institution":"Ludwig Maximilians Universitaet Muenchen","correspondingAuthor":false,"prefix":"","firstName":"Sebastian","middleName":"","lastName":"Theurich","suffix":""}],"badges":[],"createdAt":"2025-10-01 01:55:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7755612/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7755612/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93780000,"identity":"9c38d698-b4d6-407c-8d9c-2b24087dddd2","added_by":"auto","created_at":"2025-10-17 12:56:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1077527,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdipose tissue-associated serum lipid levels at the day of CAR-T infusion are associated with survival.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Schema of the discovery cohort comprising 59 patients with available body composition (pre-lymphodepletion, pre-LD) and serum metabolomics collected at baseline (Day 0), early post-treatment (Day 3–5), and intermediate follow-up (Day 14). Clinical outcomes include PFS, OS, and CRS.\u003c/p\u003e\n\u003cp\u003e(B) Flowchart of statistical analysis: Patients were stratified into high versus low AT groups. Serum metabolites underwent quality control with internal standards (lamivudine), feature selection by fold change (FC) and PLS-DA (VIP \u0026gt;1.5), and correlation filtering (±0.2) with AT compartments. The remaining metabolites were tested for outcome associations. In the volcano plot, metabolites enriched in the high-AT group are shown in red, whereas those enriched in the low-AT group are shown in blue.\u003c/p\u003e\n\u003cp\u003e(C) Forest plot summarizing HRs for metabolite groups associated with PFS. HRs were derived from multivariable Cox regression models for each metabolite, adjusting for sex, costimulatory domain, and tumor volume, and summarized using linear mixed models based on the metabolite group. Points represent combined HRs; lines indicate 95% CIs. Point size shows the number of metabolites per group; significant groups are highlighted in red.\u003c/p\u003e\n\u003cp\u003e(D) Kaplan–Meier survival curves for PFS and OS stratified by median serum levels of representative metabolites. Patients were dichotomized into high vs. low groups (N = 25 per group) based on the median levels of AC-(22:1) for acylcarnitines and PEA-(34:03) for phosphatidylethanolamines. Statistical significance between groups was assessed using the log-rank test.\u003c/p\u003e\n\u003cp\u003e(E) Stacked bar plots showing the adipose tissue compartments of origin for metabolites within lipid groups associated with PFS. The y-axis indicates the percentage of metabolites per lipid group. Colors denote metabolite origin: VAT-derived, SAT-derived, or AT-shared (detected across both depots), and metabolites identified from overall AT differences are annotated as “enriched.” The number of Adipose-Derived Metabolites Modulate CAR-T Cell Therapy Cordas dos Santos et al. metabolites included in each group is: acylcarnitines (AC, n = 12), sphingomyelins (SM, n = 4), plasmalogens (Plas, n = 3), and phosphatidylethanolamines (PEA, n = 11). (F) Scatter plots showing the relationship between normalized serum metabolite levels and visceral adipose tissue (VAT, cm\u003csup\u003e2\u003c/sup\u003e) at day 0. Each panel corresponds to one lipid class: acylcarnitines (AC, n = 12), sphingomyelins (SM, n = 4), plasmalogens (Plas, n = 3), and phosphatidylethanolamines (PEA, n = 11). Each dot represents one metabolite within the respective class. Linear regression lines depict associations for individual metabolites. The color gradient indicates the strength and direction of the Spearman correlation coefficient (red = positive correlation, blue = negative correlation). Abbreviations: CAR-T, chimeric antigen receptor T-cell; AT, adipose tissue; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; PLS-DA, partial least squares discriminant analysis; VIP, variable importance in projection; HR, hazard ratio; CI, confidence interval; PFS, progression-free survival; OS, overall survival; CRS, cytokine-release syndrome.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7755612/v1/7e99755fc93b2b237348d0a4.png"},{"id":93778795,"identity":"12db967e-56a8-46d3-aec9-2a2d0d34f2ab","added_by":"auto","created_at":"2025-10-17 12:48:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":745651,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdipose tissue-associated serum lipid levels short-term after CAR-T infusion are associated with CRS development.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Association of VAT with CRS severity in the discovery cohort (n=54). Pie chart showing CRS grade distribution. Boxplot illustrating VAT by CRS grade (0–3). Kaplan-Meier curve for cumulative incidence of CRS grade ≥2 stratified by high vs. low VAT.\u003c/p\u003e\n\u003cp\u003e(B) Forest plot summarizing ORs for lipid metabolite groups associated with CRS grade ≥2. ORs were derived from multivariable logistic regression models for each metabolite, adjusting for sex, costimulatory domain, and tumor volume, and summarized using linear mixed models based on the metabolite group. Points represent combined ORs; lines indicate 95% CIs. Point size shows the number of metabolites per group; significant groups are highlighted in red.\u003c/p\u003e\n\u003cp\u003e(C–F) Stacked bar plots and cumulative incidence curves for representative metabolites (phosphatidylethanolamines, acylcarnitines, lysophospholipids), comparing CRS distribution and Adipose-Derived Metabolites Modulate CAR-T Cell Therapy Cordas dos Santos et al. incidence of severe CRS (grade ≥2). Patients were dichotomized into high vs. low metabolite groups based on median serum levels (N = 27 per group). Bar plots show the distribution of CRS grades across groups, while cumulative incidence curves display the probability of developing CRS grade ≥2 over time after CAR-T infusion. Statistical testing was performed using Fisher’s exact test (for CRS grade distribution) and log-rank test (for incidence curves).\u003c/p\u003e\n\u003cp\u003e(G) Stacked bar plots showing the adipose tissue compartments of origin for metabolites selected within each lipid group. The y-axis indicates the percentage of metabolites per lipid group. Colors denote metabolite origin: VAT-derived, SAT-derived, or AT-shared (detected across both depots), and metabolites identified from overall AT differences are annotated as “enriched.” The number of metabolites included in each group is: acylcarnitines (AC, n = 4), lysophosphatidylcholine (LPC, n = 12), lysoPAFs n = 3, and phosphatidylethanolamines (PEA, n = 6).\u003c/p\u003e\n\u003cp\u003e(H) Scatter plot with linear associations depicting Spearman correlations between normalized serum metabolite levels and VAT amount within each lipid group on day 3-5. Color gradient represents correlation coefficient. Scatter plots showing the relationship between normalized serum metabolite levels and visceral adipose tissue (VAT, cm\u003csup\u003e2\u003c/sup\u003e) at day 3-5. Each panel corresponds to one lipid class: acylcarnitines (AC, n = 4) and phosphatidylethanolamines (PEA, n = 6). Each dot represents one metabolite within the respective class. Linear regression lines depict associations for individual metabolites. The color gradient indicates the strength and direction of the Spearman correlation coefficient (red = positive correlation, blue = negative correlation). Abbreviations: CRS, cytokine-release syndrome; VAT, visceral adipose tissue; OR, odds ratio; CI, confidence interval; AT, adipose tissue.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7755612/v1/010726fd5bed2e111388207a.png"},{"id":93778798,"identity":"32c1a91a-7b37-49e3-9d0a-d9b97f850692","added_by":"auto","created_at":"2025-10-17 12:48:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1338885,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerum lipid metabolites demonstrate different serum dynamics during CAR-T therapy and are affected by VAT amount.\u0026nbsp;\u003c/strong\u003eAdipose-Derived Metabolites Modulate CAR-T Cell Therapy Cordas dos Santos et al. Boxplots depicting serum metabolite levels at baseline (Day 0), early (Day 3–5), and intermediate (Day 14) post-CAR-T therapy, stratified by high vs. low VAT. Lipid classes include: (A) Acylcarnitines, (B) Phosphatidylethanolamines, (C) Lysophosphatidylcholines, (D) Sphingomyelins, (E) Plasmalogens, and (F) Lysophosphatidylacetyltransferases. Boxplots indicate median and 95% CI; points represent individual measurements. Lines connect medians over time. Serum metabolite levels are shown as relative abundances, calculated using lamivudine as an internal standard. Abbreviations: VAT, visceral adipose tissue; CI, confidence interval.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7755612/v1/17a0f1fa22d6604928bd415f.png"},{"id":93778801,"identity":"8f577783-19e8-4ba0-9584-ab1a4e40cb64","added_by":"auto","created_at":"2025-10-17 12:48:19","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":518784,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eValidation of an acylcarnitine-based signature predicting CRS severity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Overview of validation cohort (n=20) with body composition and serum metabolomics collected at baseline (Day -6), early (Day 2–5), and later (Day 6–8). Outcomes include PFS, OS, and CRS.\u003c/p\u003e\n\u003cp\u003e(B) Boxplots comparing VAT and SAT areas between the discovery cohort (n = 54) and the validation cohort (n = 20). Each point represents one patient. Boxes indicate the interquartile range (IQR), whiskers the 1.5×IQR, and horizontal lines the median. Group differences were assessed using the Wilcoxon rank-sum test.\u003c/p\u003e\n\u003cp\u003e(C) Pie chart illustrating CRS grade distribution in the validation cohort.\u003c/p\u003e\n\u003cp\u003e(D) Boxplots comparing VAT and SAT areas in patients with CRS grade ≥2 (n = 6) versus CRS grade 0–1 (n = 14). Each point represents one patient. Boxes indicate the interquartile range (IQR), whiskers the 1.5×IQR, and horizontal lines the median. Group differences were assessed using the Wilcoxon rank-sum test.\u003c/p\u003e\n\u003cp\u003e(E) Kaplan–Meier curves showing the cumulative incidence of CRS grade ≥2 stratified by VAT area. Patients were dichotomized into high versus low VAT groups using the median as a cutoff (n = 10 per group). Statistical significance between groups was assessed using the log-rank test. Adipose-Derived Metabolites Modulate CAR-T Cell Therapy Cordas dos Santos et al.\u003c/p\u003e\n\u003cp\u003e(F) Forest plot validating odds ratios (ORs) for severe CRS (grade ≥2) across lipid groups in the validation cohort. ORs for individual metabolites were derived from multivariable logistic regression models adjusting for sex and CAR costimulatory domain. Group-level ORs were then summarized using linear mixed-effects models based on metabolite class. Points represent OR estimates and horizontal lines indicate 95% confidence intervals. Lipid groups with statistically significant associations are highlighted in red.\u003c/p\u003e\n\u003cp\u003e(G) Acylcarnitine signature (AC-score) based on the sum of four metabolites above their respective median serum levels. Left: Kaplan–Meier curve showing the cumulative incidence of CRS grade ≥2 stratified by high versus low AC-score. Right: stacked bar plot displaying the distribution of CRS grades across groups. Patient numbers per group: AC-score = 0 (n = 2), AC-score = 1–2 (n = 9), AC-score = 3–4 (n = 5). Statistical testing was performed using the log-rank test (incidence) and Fisher’s exact test (distribution).\u003c/p\u003e\n\u003cp\u003e(H) Kaplan–Meier survival curves showing the association of the AC score with PFS and OS in the validation cohort. Patients were stratified by AC-score groups (AC-score = 0, n = 1; AC-score = 1–2, n = 6; AC-score = 3–4, n = 5). Survival differences between groups were assessed using the log-rank test.\u003c/p\u003e\n\u003cp\u003eAbbreviations: CRS, cytokine-release syndrome; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; OR, odds ratio; CI, confidence interval; AC-score, acylcarnitine score; PFS, progression-free survival; OS, overall survival.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7755612/v1/685c010a4f61a43240b78272.png"},{"id":93780001,"identity":"719d49b3-f463-4d09-8e9b-22fa55ba6b22","added_by":"auto","created_at":"2025-10-17 12:56:18","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1926209,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSingle-cell RNA-sequencing of adipocyte-co-cultured bone marrow immune cells identifies an upregulation of pro-inflammatory pathways in T-cells and macrophages.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Experimental design of the in vitro experiments. Isolated bone marrow cells (BMCs) were co-cultured with the 3T3-L1 cell line or its adipocytic differentiated version for 16 days and then harvested for single-cell RNA-sequencing (scRNA-seq). Adipose-Derived Metabolites Modulate CAR-T Cell Therapy Cordas dos Santos et al.\u003c/p\u003e\n\u003cp\u003e(B) A total of 13,325 cells from six samples were embedded into a two-dimensional space by the Uniform Manifold Approximation and Projection (UMAP) method. Cells are colored according to the coarse annotation of the cell identities.\u003c/p\u003e\n\u003cp\u003e(C-D) UMAP is color-coded by cell type marker, enrichment score of proliferation markers (for G2/M and S phase), and co-culture condition.\u003c/p\u003e\n\u003cp\u003e(E/G) Volcano plots illustrating up- and downregulated genes of T-cells (E) and macrophages (G) co-cultured with adipocytes compared to those co-cultured with fibroblasts. Significantly upregulated genes are colored in red; significantly downregulated genes are colored in blue. The Wilcoxon rank sum test was used for statistical testing, with an adjusted p-value of below 0.1 deemed significant.\u003c/p\u003e\n\u003cp\u003e(F/H) Bar plots illustrating gene ontology term (for biological processes) enrichment analysis for differentially expressed genes of T-cells (F) and macrophages (H) co-cultured with adipocytes compared to those co-cultured with fibroblasts from E-F. Circle size indicates the absolute number of genes contributing to each term, and the red color scale reflects the strength of enrichment (adjusted p-value).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7755612/v1/253ceef8cc23ad9c43018a8f.png"},{"id":95654082,"identity":"dc1b2ac7-990d-4174-824b-7974b5957130","added_by":"auto","created_at":"2025-11-11 16:09:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3257002,"visible":true,"origin":"","legend":"Article File","description":"","filename":"NatMetCARTMetabolomicsManuscript250930.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7755612/v1_covered_2942b8d7-809a-42ea-b174-2a9b1ec89926.pdf"},{"id":93778796,"identity":"4b11eca1-f530-4919-b538-b28345ed400f","added_by":"auto","created_at":"2025-10-17 12:48:18","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1146066,"visible":true,"origin":"","legend":"Nature Reporting Summary","description":"","filename":"NatMetCARTMetabolomicsReportingSummary250927.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7755612/v1/ae92178f8285cf5ebffe2730.pdf"},{"id":93778800,"identity":"42c375af-1aa2-456f-bf35-c72c25a67abb","added_by":"auto","created_at":"2025-10-17 12:48:18","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1939021,"visible":true,"origin":"","legend":"Supplementary Files","description":"","filename":"NatMetCARTMetabolomicsSupplFiles250930.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7755612/v1/14912ec9f51e265adf2729d1.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nD.M.C.D.S. Regeneron: Research funding. Pending provisional US patent filed in 2024 (U.S. Patent Application No. 63/716,000).\r\nK.R. Kite/Gilead: Research Funding, Consultancy, Honoraria and travel support; Novartis: Honoraria; BMS/Celgene: Consultancy, Honoraria; Pierre-Fabre: Travel support. CSL Behring: Consultancy. \r\nM.S. Education Grants: BMS, Gilead/Kite, Johnson and Johnson, Novartis. Honoraria: Gilead/Kite. Advisory Boards: Interius, Takeda, Gilead/Kite, Novartis, BMS. \r\nS.T. Consulting Fees: Johnson \u0026 Johnson, Pfizer, Sanofi, Menarini Stemline, Oncopeptides, Bristol-Myers-Squibb, Glaxo-Smith-Kline, Takeda, Kyowa Kirin. Payment for Expert Testimony: Johnson \u0026 Johnson, Pfizer, Sanofi, Menarini Stemline, Oncopeptides, Bristol-Myers-Squibb, Glaxo-Smith-Kline, Takeda, Kyowa Kirin. Travel Support: Johnson \u0026 Johnson, Pfizer, Sanofi, Menarini Stemline, Oncopeptides, Bristol-Myers-Squibb, Glaxo-Smith-Kline, Takeda, Kyowa Kirin. \r\nThe remaining authors have nothing to declare. None of the mentioned conflicts of interest were related to the financing of the content of this manuscript.","formattedTitle":"Adipose Tissue-Associated Lipid Serum Signatures Modulate Efficacy and Toxicity of CAR-T Cell Therapy in Lymphoid Malignancies","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"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},"keywords":"Adipose Tissue, Body Composition, Chimeric Antigen Receptor, Lipidomics, Serum Metabolomics","lastPublishedDoi":"10.21203/rs.3.rs-7755612/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7755612/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The host metabolic state is a key regulator of immune cell function and may influence outcomes of T-cell–based therapies. To investigate the role of adiposity in CAR-T cell therapy, we integrated computed tomography–based body composition analysis with targeted mass spectrometry of 158 longitudinal serum samples from 54 patients with relapsed B-cell lymphoma. We identify distinct adipose tissue–associated lipid classes linked to survival and the development of cytokine release syndrome (CRS), with visceral adiposity–dependent dynamics during therapy. Among these, associations between acylcarnitines and phosphatidylethanolamines with CRS were independently validated in a separate cohort of 17 patients with B-cell lymphoma and myeloma. In parallel, single-cell RNA sequencing of murine bone marrow immune cells in vitro cultured under obesity-mimicking conditions revealed a pro-inflammatory transcriptional program in key immune cell subsets, implicating adipose-derived metabolic signals in immune modulation. These findings highlight a link between host metabolic and body compositional states and CAR-T function and support the integration of metabolic profiling into precision immunotherapy.","manuscriptTitle":"Adipose Tissue-Associated Lipid Serum Signatures Modulate Efficacy and Toxicity of CAR-T Cell Therapy in Lymphoid Malignancies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 12:48:12","doi":"10.21203/rs.3.rs-7755612/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":"4e0777e4-ea38-4c3e-a09d-89d5786c9d3f","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56420500,"name":"Health sciences/Oncology/Cancer/Haematological cancer"},{"id":56420501,"name":"Health sciences/Oncology/Cancer/Cancer therapy/Cancer immunotherapy"},{"id":56420502,"name":"Health sciences/Medical research/Translational research"},{"id":56420503,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity"}],"tags":[],"updatedAt":"2025-11-10T10:28:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 12:48:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7755612","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7755612","identity":"rs-7755612","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}