{"doi":"10.1136/jitc-2022-005020","title":"Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy","abstract":"BACKGROUND: Current immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy. METHODS: Senescent T cell populations in the TMEs in mouse lung cancer, breast cancer, and melanoma tumor models were evaluated. Furthermore, T cell senescence induced by mouse tumor and regulatory T (Treg) cells in vitro was determined with multiple markers and assays, including real-time PCR, flow cytometry, and histochemistry staining. Loss-of-function strategies with pharmacological inhibitors and the knockout mouse model were used to identify the potential molecules and pathways involved in T cell senescence. In addition, melanoma mouse tumor immunotherapy models were performed to explore the synergistical efficacy of antitumor immunity via prevention of tumor-specific T cell senescence combined with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy. RESULTS: We report that both mouse malignant tumor cells and Treg cells can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling. Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo. CONCLUSIONS: These studies prove the novel concept that targeting both effector T cell senescence and exhaustion is an effective strategy and can synergistically enhance cancer immunotherapy.","journal":"Journal for ImmunoTherapy of Cancer","year":2022,"id":234635,"datarank":0.6846522287201755,"base_score":4.564348191467836,"endowment":4.564348191467836,"self_citation_contribution":0.6846522287201755,"citation_network_contribution":0.0,"self_endowment_contribution":0.6846522287201755,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":95,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"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":620459,"name":"Fusheng Si","orcid":"0000-0001-8719-7704","position":1,"is_corresponding":false},{"id":850896,"name":"David M. Bagley","orcid":"0000-0002-1191-1278","position":2,"is_corresponding":false},{"id":645683,"name":"Feiya Ma","orcid":null,"position":3,"is_corresponding":false},{"id":850897,"name":"Yuanqin Zhang","orcid":"0000-0002-6841-0693","position":4,"is_corresponding":false},{"id":572064,"name":"Yan Tao","orcid":null,"position":5,"is_corresponding":false},{"id":850898,"name":"Emily Shaw","orcid":"0000-0003-1424-7568","position":6,"is_corresponding":false},{"id":272242,"name":"Guangyong Peng","orcid":"0000-0001-7268-0234","position":7,"is_corresponding":false},{"id":272241,"name":"Xia Liu","orcid":"0000-0002-5372-1245","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:21:42.662304Z","pmid":"36192086","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":[]}