{"doi":"10.1101/2021.06.07.447379","title":"Hypoxia is a dominant remodeler of the CD8 <sup>+</sup> T cell surface proteome relative to activation and regulatory T cell-mediated suppression","abstract":"ABSTRACT Immunosuppressive factors in the tumor microenvironment (TME) impair T cell function and limit the anti-tumor immune response. T cell surface receptors that influence interactions and function in the TME are already proven targets for cancer immunotherapy. However, surface proteome remodeling of primary human T cells in response to suppressive forces in the TME has never been characterized systematically. Using a reductionist cell culture approach with primary human T cells and SILAC-based quantitative cell surface capture glycoproteomics, we examined how two immunosuppressive TME factors, regulatory T cells (Tregs) and hypoxia, globally affect the activated CD8 + surface proteome (surfaceome). Surprisingly, the CD8 + /Treg co-culture only modestly affected the CD8 + surfaceome, but did reverse several activation-induced surfaceomic changes. In contrast, hypoxia dramatically altered the CD8 + surfaceome in a manner consistent with both metabolic reprogramming and induction of an immunosuppressed state. The CD4 + T cell surfaceome similarly responded to hypoxia, revealing a novel hypoxia-induced surface receptor program. Our findings are consistent with the premise that hypoxic environments create a metabolic challenge for T cell activation, which may underlie the difficulty encountered in treating solid tumors with immunotherapies. Together, the data presented here provide insight into how suppressive TME factors remodel the T cell surfaceome and represent a valuable resource to inform future therapeutic efforts to enhance T cell function in the TME.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":225268,"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":0.9559,"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":566381,"name":"Amy M. Weeks","orcid":"0000-0003-4700-8256","position":1,"is_corresponding":false},{"id":240952,"name":"Eric Shifrut","orcid":"0000-0001-6827-0128","position":2,"is_corresponding":false},{"id":625671,"name":"Julia Carnevale","orcid":"0000-0001-9410-7148","position":3,"is_corresponding":false},{"id":292905,"name":"Lisa L. Kirkemo","orcid":"0000-0003-1686-6987","position":4,"is_corresponding":false},{"id":7895,"name":"Alan Ashworth","orcid":"0000-0003-1446-7878","position":5,"is_corresponding":false},{"id":30775,"name":"Alexander Marson","orcid":"0000-0002-2734-5776","position":6,"is_corresponding":false},{"id":237520,"name":"James A. Wells","orcid":"0000-0001-8267-5519","position":7,"is_corresponding":false},{"id":274317,"name":"James R. Byrnes","orcid":"0000-0003-0297-1209","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-18T23:54:26.581453Z","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":[]}