{"doi":"10.3389/fimmu.2021.660944","title":"Hypoxia Supports Differentiation of Terminally Exhausted CD8 T Cells","abstract":"Hypoxia, angiogenesis, and immunosuppression have been proposed to be interrelated events that fuel tumor progression and impair the clinical effectiveness of anti-tumor therapies. Here we present new mechanistic data highlighting the role of hypoxia in fine-tuning CD8 T cell exhaustion in vitro , in an attempt to reconcile seemingly opposite evidence regarding the impact of hypoxia on functional features of exhausted CD8 T cells. Focusing on the recently characterized terminally-differentiated and progenitor exhausted CD8 T cells, we found that both hypoxia and its regulated mediator, vascular endothelial growth factor (VEGF)-A, promote the differentiation of PD-1 + TIM-3 + CXCR5 + terminally exhausted-like CD8 T cells at the expense of PD-1 + TIM-3 - progenitor-like subsets without affecting tumor necrosis factor (TNF)-α and interferon (IFN)-γ production or granzyme B (GZMB) expression by these subpopulations. Interestingly, hypoxia accentuated the proangiogenic secretory profile in exhausted CD8 T cells. VEGF-A was the main factor differentially secreted by exhausted CD8 T cells under hypoxic conditions. In this sense, we found that VEGF-A contributes to generation of terminally exhausted CD8 T cells during in vitro differentiation. Altogether, our findings highlight the reciprocal regulation between hypoxia, angiogenesis, and immunosuppression, providing a rational basis to optimize synergistic combinations of antiangiogenic and immunotherapeutic strategies, with the overarching goal of improving the efficacy of these treatments.","journal":"Frontiers in Immunology","year":2021,"id":150977,"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":87,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9444,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":281684,"name":"Tomás Dalotto‐Moreno","orcid":"0000-0001-6179-2185","position":1,"is_corresponding":false},{"id":643378,"name":"Lucía Kindgard","orcid":null,"position":2,"is_corresponding":false},{"id":641873,"name":"Pablo Andrés García","orcid":"0000-0003-1900-1831","position":3,"is_corresponding":false},{"id":641874,"name":"Ada G. Blidner","orcid":"0000-0002-1092-3656","position":4,"is_corresponding":false},{"id":641875,"name":"Karina V. Mariño","orcid":"0000-0002-0581-8640","position":5,"is_corresponding":false},{"id":281692,"name":"Gabriel A. Rabinovich","orcid":"0000-0002-0947-8735","position":6,"is_corresponding":false},{"id":641876,"name":"Diego O. Croci","orcid":"0000-0002-8623-0645","position":7,"is_corresponding":false},{"id":641872,"name":"Nadia Bannoud","orcid":"0000-0001-8540-5995","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-18T23:43:11.293086Z","pmid":"34025660","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":[]}