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

  • J Immunother Cancer. 2022 Nov;10(11):e004806. doi: 10.1136/jitc-2022-004806.
Khalid W Kalim  1 ,  Jun-Qi Yang  1 ,  Mark Wunderlich  1 ,  Vishnu Modur  1 ,  Phuong Nguyen  1 ,  Yuan Li  1 ,  Ting Wen  2 ,  Ashley Kuenzi Davis  1 ,  Ravinder Verma  1 ,  Qing Richard Lu  1 ,  Anil G Jegga  3 ,  Yi Zheng  4 ,  Fukun Guo  4
Affiliations
  • 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 Allergy and Immunology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • 3. Division of Biomedical Informatics, 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 [email protected] [email protected].
PMID: 36427906 DOI: 10.1136/jitc-2022-004806
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.

Keywords
T-Lymphocytes; adaptive immunity; immunotherapy; lymphocytes, tumor-infiltrating.
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