{"doi":"10.1101/2022.03.21.485049","title":"The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity","abstract":"ABSTRACT The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 coimmunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary costimulatory signals required for response to PD-1 blockade (e.g. CD28 ), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2 -expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":297345,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"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":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":24144,"name":"Johannes C. Melms","orcid":"0000-0002-5410-6586","position":1,"is_corresponding":false},{"id":98182,"name":"Meri Rogava","orcid":"0000-0002-0314-5323","position":2,"is_corresponding":false},{"id":6109,"name":"Chris J. Frangieh","orcid":null,"position":3,"is_corresponding":false},{"id":350508,"name":"Shivem B. Shah","orcid":"0000-0001-9439-6509","position":4,"is_corresponding":false},{"id":843189,"name":"Zachary Walsh","orcid":null,"position":5,"is_corresponding":false},{"id":277289,"name":"Oleksandr Kyrysyuk","orcid":"0000-0002-7646-6363","position":6,"is_corresponding":false},{"id":79597,"name":"Amit Dipak Amin","orcid":"0000-0002-2613-2082","position":7,"is_corresponding":false},{"id":842246,"name":"Lindsay Caprio","orcid":"0000-0003-1370-8684","position":8,"is_corresponding":false},{"id":706114,"name":"Benjamin T. Fullerton","orcid":"0000-0001-7422-5120","position":9,"is_corresponding":false},{"id":556577,"name":"Rajesh Soni","orcid":null,"position":10,"is_corresponding":false},{"id":266897,"name":"Casey R. Ager","orcid":"0000-0003-0507-700X","position":11,"is_corresponding":false},{"id":79598,"name":"Jana Biermann","orcid":"0000-0002-8907-4633","position":12,"is_corresponding":false},{"id":255065,"name":"Yi‐Ping Wang","orcid":"0000-0001-9574-2194","position":13,"is_corresponding":false},{"id":842250,"name":"Michael Mu","orcid":"0000-0003-4035-5298","position":14,"is_corresponding":false},{"id":985960,"name":"Hijab Fatima","orcid":null,"position":15,"is_corresponding":false},{"id":886067,"name":"Emily K. Moore","orcid":"0000-0003-2186-5647","position":16,"is_corresponding":false},{"id":236123,"name":"Neil Vasan","orcid":"0000-0003-1779-484X","position":17,"is_corresponding":false},{"id":226862,"name":"Samuel F. Bakhoum","orcid":"0000-0002-4779-8422","position":18,"is_corresponding":false},{"id":604503,"name":"Steven L. Reiner","orcid":"0000-0002-1635-8619","position":19,"is_corresponding":false},{"id":72145,"name":"Chantale Bernatchez","orcid":"0000-0001-5926-3460","position":20,"is_corresponding":false},{"id":225937,"name":"Emily M. Mace","orcid":"0000-0003-0226-7393","position":21,"is_corresponding":false},{"id":24148,"name":"Kai W. Wucherpfennig","orcid":"0000-0002-1829-302X","position":22,"is_corresponding":false},{"id":5602,"name":"Dirk Schadendorf","orcid":"0000-0003-3524-7858","position":23,"is_corresponding":false},{"id":241729,"name":"Gary K. Schwartz","orcid":"0000-0003-1813-5061","position":24,"is_corresponding":false},{"id":5593,"name":"Benjamin Izar","orcid":"0000-0003-2379-6702","position":25,"is_corresponding":false},{"id":501382,"name":"Patricia Ho","orcid":"0000-0002-4622-8188","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:26.161109Z","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":[]}