TY - JOUR T1 - Targeting of Cdc42 GTPase in regulatory T cells unleashes antitumor T-cell immunity JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2022-004806 VL - 10 IS - 11 SP - e004806 AU - Khalid W Kalim AU - Jun-Qi Yang AU - Mark Wunderlich AU - Vishnu Modur AU - Phuong Nguyen AU - Yuan Li AU - Ting Wen AU - Ashley Kuenzi Davis AU - Ravinder Verma AU - Qing Richard Lu AU - Anil G Jegga AU - Yi Zheng AU - Fukun Guo Y1 - 2022/11/01 UR - http://jitc.bmj.com/content/10/11/e004806.abstract N2 - 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.All data relevant to the study are included in the article or uploaded as supplementary information. ER -