{"doi":"10.7150/thno.101107","title":"Tumor growth suppression in adoptive T cell therapy via IFN-γ targeting of tumor vascular endothelial cells","abstract":"Rationale:In adoptive T cell therapy (ACT), the direct cytotoxic effects of CD8 T cells on tumor cells, including the release of interferon-gamma (IFN-), are considered the primary mechanism for tumor eradication.Cancer antigen escape diminishes the T cell responses, thereby limiting the therapeutic success.The impacts of IFN- targeting non-tumor cells in ACT, on the other hand, remains under-investigated.We hypothesized that IFN- action on non-tumor cells, particularly tumor vascular endothelial cells within the physiological tumor microenvironment, could influence therapeutic efficacy.Methods: ACT was performed against ovalbumin (OVA)-or OVA-peptide SIINFEKL-expressing syngeneic mouse tumors, MCA-205-OVA-GFP fibrosarcoma or MOC2-SIINFEKL oral squamous cell carcinoma, using ex vivo-activated OT-1 CD8 T cells expressing the T cell receptor against OVA.Efficacy was examined in wild-type mice, mice deficient for IFN- receptor 1 (IFN-R1KO), and bone marrow chimeras lacking IFN-R1 expression in endothelial cells.To exclude direct IFN- action against tumor cells, IFN-R1KO-MCA-205-OVA-GFP tumors were used.IFN- production, STAT1 induction in its targets, and subsequent changes, especially in vasculatures in the tumor, were examined.Results: ACT suppressed the growth of MCA-205-OVA-GFP and MOC2-SIINFEKL tumors in wild-type mice but failed in IFNR1KO mice.Furthermore, in the bone marrow chimeras lacking endothelial cell IFN-R1, ACT efficacy was lost, thus implicating a vital role of IFN- action on the endothelium.IFN-R1KO-MCA-205-OVA-GFP tumor growth was successfully suppressed by ACT in wild-type mice, suggesting that IFN- targeting of tumor cells may not be essential for ACT efficacy.OT-1 CD8 T cells interacted with endothelial cells or localized in proximity to the vessels on Day 1.5 after transfer, as observed by intravital microscopy.The OT-1 T cells found in tumors were limited in number but produced high levels of IFN- on Day 1.5, while their number peaked on Day 5.5 with negligible IFN- production.Together with IFN- production by endogenous lymphocytes, IFN- levels in the whole tumor peaked on Day 1.5, inducing IFN-/STAT1 signaling in endothelial cells.Early targeting of tumor vascular endothelial cells by IFN- led to endothelial regression, reduced perfusion, and tumor hypoxia/necrosis (Day 4.5-7).Conclusions: These findings highlight the critical role of T cell-derived IFN- action on endothelial cells early in ACT, emphasizing its dynamic influence on the tumor microenvironment, and offering insights into addressing antigen escape.","journal":"Theranostics","year":2024,"id":458654,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":687056,"name":"Colleen P. Olkowski","orcid":"0000-0002-2370-0582","position":1,"is_corresponding":false},{"id":110328,"name":"Peter L. Choyke","orcid":"0000-0003-1086-8826","position":2,"is_corresponding":false},{"id":342836,"name":"Noriko Sato","orcid":"0000-0002-9372-1725","position":3,"is_corresponding":false},{"id":1284915,"name":"Qiaoya Lin","orcid":"0000-0003-2334-5602","position":0,"is_corresponding":true}],"reference_count":1,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:03:50.608887Z","pmid":"39629126","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":[]}