{"doi":"10.1126/scitranslmed.add1868","title":"FcγRIIB expressed on CD8<sup>+</sup>T cells limits responsiveness to PD-1 checkpoint inhibition in cancer","abstract":"Checkpoint inhibition using Fc-containing monoclonal antibodies has emerged as a powerful therapeutic approach to augment antitumor immunity. We recently showed that FcγRIIB, the only inhibitory IgG-Fc receptor, is expressed on a population of highly differentiated effector CD8 + T cells in the tumors of mice and humans, raising the possibility that CD8 + T cell responses may be directly modulated by checkpoint inhibitor binding to T cell–expressed FcγRIIB. Here, we show that despite exhibiting strong proliferative and cytokine responses at baseline, human FcγRIIB pos CD8 + T cells exhibited reduced responsiveness to both PD-1 and CTLA-4 checkpoint inhibition as compared with FcγRIIB neg CD8 + T cells in vitro. Moreover, frequencies of FcγRIIB pos CD8 + T cells were reduced after treatment of patients with melanoma with nivolumab in vivo. This reduced responsiveness was FcγRIIB dependent, because conditional genetic deletion of FcγRIIB on tumor-specific CD8 + T cells improved response to checkpoint blockade in B16 and LLC mouse models of cancer. The limited responsiveness of FcγRIIB pos CD8 + T cells was also dependent on an intact Fc region of the checkpoint inhibitor, in that treatment with Fc-devoid anti–PD-1 F(ab) fragments resulted in increased proliferation of FcγRIIB pos CD8 + T cells, without altering the response of FcγRIIB neg CD8 + T cells. Last, the addition of FcγRIIB blockade improved efficacy of PD-1 checkpoint inhibition in mouse models of melanoma, lung, and colon cancer. These results illuminate an FcγRIIB-mediated, cell-autonomous mechanism of CD8 + T cell suppression, which limits the efficacy of checkpoint inhibitors during antitumor immune responses in vivo.","journal":"Science Translational Medicine","year":2023,"id":334766,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9458,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":695464,"name":"Marvi Tariq","orcid":"0000-0001-5286-495X","position":1,"is_corresponding":false},{"id":314036,"name":"Megan M. Wyatt","orcid":"0000-0003-1316-260X","position":2,"is_corresponding":false},{"id":1063670,"name":"Charlotte Duneton","orcid":"0000-0002-0603-1970","position":3,"is_corresponding":false},{"id":796025,"name":"Kirsten Baecher","orcid":"0000-0001-6477-7968","position":4,"is_corresponding":false},{"id":314041,"name":"Chrystal M. Paulos","orcid":"0000-0002-0784-2601","position":5,"is_corresponding":false},{"id":449565,"name":"Ragini R. Kudchadkar","orcid":"0000-0001-9070-5052","position":6,"is_corresponding":false},{"id":574693,"name":"Michael Lowe","orcid":"0000-0003-4853-7352","position":7,"is_corresponding":false},{"id":270266,"name":"Mandy L. Ford","orcid":"0000-0001-6736-4421","position":8,"is_corresponding":false},{"id":695465,"name":"Kelsey B. Bennion","orcid":"0000-0001-5735-991X","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T01:09:53.742667Z","pmid":"37611081","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":[]}