{"doi":"10.1101/2021.09.23.461402","title":"Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity","abstract":"Abstract 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 utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor 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 cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes antitumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy. Significance Effector T lymphocytes promote autoimmune diseases but have potential to kill tumor cells. However, cancer cells can evade T cell-mediated killing in part by utilizing regulatory T (Treg) cells to inhibit effector T cell function. Here we show that Treg cell-specific heterozygous deletion of Cdc42 gene that encodes Cdc42 GTPase dampens Treg cell fitness through carbonic anhydrase I-mediated pH changes, leading to anti-tumor T cell immunity. Pharmacological targeting of Cdc42 mimics genetic deletion of Cdc42 in impairing Treg cell fitness and evoking anti-tumor T cell immunity. Importantly, Cdc42 targeting does not appear to cause systemic autoimmunity. Given that current cancer immunotherapies only demonstrate limited clinical efficacies, our findings may open a new avenue for cancer immunotherapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":226855,"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":0.9467,"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":830689,"name":"Jun-Qi Yang","orcid":null,"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":263829,"name":"Q. Richard Lu","orcid":"0000-0001-6846-9014","position":9,"is_corresponding":false},{"id":311191,"name":"Anil G. Jegga","orcid":"0000-0002-4881-7752","position":10,"is_corresponding":false},{"id":830212,"name":"Yi Zheng","orcid":"0000-0002-4877-4289","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":37,"raw_metadata":null,"created_at":"2026-07-18T23:54:38.004707Z","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":[]}