(1) Kalim KW (2) Yang JQ (3) Wunderlich M (4) Modur V (5) Nguyen P (6) Li Y (7) Wen T (8) Davis AK (9) Verma R (10) Lu QR (11) Jegga AG (12) Zheng Y (13) Guo F

Journal for immunotherapy of cancer

Kalim and Yang et al. showed that while homozygous knockout of Cdc42 in Tregs induced Treg cell death and autoimmunity, heterozygous knockout induced Treg instability and effector T reprogramming (loss of Foxp3, enhanced memory, increased effector phenotype, reduced suppressive function) through a carbonic anhydrase-I (CAI)-mediated pH change (regulated by WASP and GATA3). This resulted in a net increase in effector CD4+ and CD8+ T cells, which mediated enhanced antitumor immunity without inducing autoimmunity. Inhibition of Cdc42 using CASIN (within a certain titration window) induced similar effects, and was additive in combination with anti-PD-1.

Contributed by Lauren Hitchings

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.

Author Info: (1) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinna

Author Info: (1) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (2) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (3) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (4) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (5) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (6) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (7) Division of Allergy and Immunology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (8) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (9) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (10) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (11) Division of Biomedical Informatics, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (12) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA fukun.guo@cchmc.org yi.zheng@cchmc.org. (13) Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA fukun.guo@cchmc.org yi.zheng@cchmc.org.

Citation: J Immunother Cancer 2022 Nov 10: Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/36427906

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