{"doi":"10.1136/jitc-2022-004806","title":"Targeting of Cdc42 GTPase in regulatory T cells unleashes antitumor T-cell immunity","abstract":"BACKGROUND: Cancer immunotherapy has taken center stage in cancer treatment. However, the current immunotherapies only benefit a small proportion of patients with cancer, necessitating better understanding of the mechanisms of tumor immune evasion and improved cancer immunotherapy strategies. Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T-cell function. In the tumor microenvironment, Treg cells are used by tumor cells to counteract effector T cell-mediated tumor suppression. Targeting Treg cells may thus unleash the antitumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T-cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit patients with cancer. METHODS: Treg cells from Treg cell-specific heterozygous Cdc42 knockout mice, C57BL/6 mice treated with a Cdc42 inhibitor CASIN, and control mice were examined for their homeostasis and stability by flow cytometry. The autoimmune responses in Treg cell-specific heterozygous Cdc42 knockout mice, CASIN-treated C57BL/6 mice, and control mice were assessed by H&E staining and ELISA. Antitumor T-cell immunity in Treg cell-specific heterozygous Cdc42 knockout mice, CASIN-treated C57BL/6 mice, humanized NSGS mice, and control mice was assessed by challenging the mice with MC38 mouse colon cancer cells, KPC mouse pancreatic cancer cells, or HCT116 human colon cancer cells. RESULTS: Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 with CASIN does not affect Treg cell numbers but induces Treg cell instability, leading to antitumor T-cell immunity without detectable autoimmune reactions. Cdc42 targeting causes an additive effect on immune checkpoint inhibitor anti-programmed cell death protein-1 antibody-induced T-cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell instability and unleashes antitumor T-cell immunity through carbonic anhydrase I-mediated pH changes. CONCLUSIONS: Rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.","journal":"Journal for ImmunoTherapy of Cancer","year":2022,"id":244638,"datarank":0.5050943744979712,"base_score":3.367295829986474,"endowment":3.367295829986474,"self_citation_contribution":0.5050943744979712,"citation_network_contribution":0.0,"self_endowment_contribution":0.5050943744979712,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"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":765848,"name":"Jun‐Qi Yang","orcid":"0000-0002-4510-8117","position":1,"is_corresponding":false},{"id":108554,"name":"Mark Wunderlich","orcid":"0000-0002-2166-5146","position":2,"is_corresponding":false},{"id":765849,"name":"Vishnu Modur","orcid":"0000-0002-5422-2552","position":3,"is_corresponding":false},{"id":312434,"name":"Phuong Nguyen","orcid":"0000-0003-2830-5677","position":4,"is_corresponding":false},{"id":765850,"name":"Yuan Li","orcid":"0000-0001-9934-7634","position":5,"is_corresponding":false},{"id":663123,"name":"Ting Wen","orcid":"0009-0006-7209-5565","position":6,"is_corresponding":false},{"id":639067,"name":"Ashley Kuenzi Davis","orcid":"0000-0003-1162-3994","position":7,"is_corresponding":false},{"id":830211,"name":"Ravinder Verma","orcid":"0000-0002-4146-152X","position":8,"is_corresponding":false},{"id":452530,"name":"Qing Lü","orcid":"0000-0002-4088-6200","position":9,"is_corresponding":false},{"id":311191,"name":"Anil G. Jegga","orcid":"0000-0002-4881-7752","position":10,"is_corresponding":false},{"id":333757,"name":"Yi Zheng","orcid":"0000-0001-7089-6074","position":11,"is_corresponding":false},{"id":703403,"name":"Fukun Guo","orcid":"0000-0002-8820-7633","position":12,"is_corresponding":false},{"id":765847,"name":"Khalid W. Kalim","orcid":"0000-0003-3433-8440","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:23:30.364338Z","pmid":"36427906","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":[]}