Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

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. SignificanceEffector 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.