{"doi":"10.1093/jimmun/vkaf283.216","title":"GPR65 inactivation in tumor cells drives antigen-independent CAR-T cell resistance via macrophage remodeling 2281","abstract":"Abstract Description Chimeric antigen receptor (CAR)-T cell therapies can be curative for CD19+ hematological malignancies, though are limited by frequent patient relapse and response failures. Here, we identify GPR65 as a tumor-specific determinant of responsiveness to CAR-T cell therapy. In patients and an immune competent mouse model of B cell acute lymphoblastic leukemia (B-ALL) CAR-T cell therapy, low GPR65 is associated with CD19+ CAR-T resistance. GPR65 knockout (GPR65 KO) tumors are likewise resistant to CAR-T cell therapy in mice. Single-cell network analyses reveal that GPR65 deficiency remodels tumor interactions with host macrophages, partially through increases in tumor VEGFA. This leads to increased macrophage numbers and preferential M2 macrophage polarization. Either depletion of host macrophages or deletion of VEGFA from GPR65 KO tumors restores responsiveness to CAR-T cell treatment. Anti-VEGFA therapy in combination with CAR-T cell administration also prolongs the survival of GPR65 KO tumor-bearing mice. Our results highlight the dramatic influence of tumor gene expression on the tumor microenvironment, its influence on CAR-T cell responsiveness, and supports new approaches to identify and overcome CAR-T cell resistance in B-ALL. Funding Sources This work was supported by funding from American Lebanese Syrian Associated Charities (ALSAC), The Assisi Foundation of Memphis, and the National Institutes of Health grant R01GM134382 and U01CA264610 (to J.Y.). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)","journal":"The Journal of Immunology","year":2025,"id":582253,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":287644,"name":"Yogesh Dhungana","orcid":"0000-0002-4021-0075","position":1,"is_corresponding":false},{"id":55257,"name":"Jiyang Yu","orcid":"0000-0003-1244-4429","position":2,"is_corresponding":false},{"id":665303,"name":"Terrence L. Geiger","orcid":"0000-0001-8290-5732","position":3,"is_corresponding":false},{"id":1494044,"name":"Jayadev Mavuluri","orcid":"0000-0001-9288-1025","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:58:55.657290Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}