2. Academic Validation
  3. Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance

Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance

  • Cell Rep. 2023 Mar 30;42(4):112314. doi: 10.1016/j.celrep.2023.112314.
Xueliang Gao 1,  Yongxia Wu 2,  Joel M Chick 3,  Andrea Abbott 4,  Baishan Jiang 5,  David J Wang 6,  Susana Comte-Walters 7,  Roger H Johnson 8,  Nathaniel Oberholtzer 9,  Michael I Nishimura 10,  Steven P Gygi 3,  Anand Mehta 11,  Denis C Guttridge 6,  Lauren Ball 7,  Shikhar Mehrotra 4,  Piotr Sicinski 12,  Xue-Zhong Yu 13,  Haizhen Wang 14
Affiliations

Affiliations

  • 1 Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: gaox@musc.edu.
  • 2 Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 3 Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
  • 4 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02215, USA.
  • 6 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 7 Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 8 Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • 9 Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 10 Department of Surgery, Loyola University Chicago, Maywood, IL 60153, USA.
  • 11 Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 12 Department of Cancer Biology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 13 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 14 Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: wangha@musc.edu.
PMID: 37000627 DOI: 10.1016/j.celrep.2023.112314
Abstract

Elucidating the mechanisms of resistance to immunotherapy and developing strategies to improve its efficacy are challenging goals. Bioinformatics analysis demonstrates that high CDK6 expression in melanoma is associated with poor progression-free survival of patients receiving single-agent immunotherapy. Depletion of CDK6 or cyclin D3 (but not of CDK4, cyclin D1, or D2) in cells of the tumor microenvironment inhibits tumor growth. CDK6 depletion reshapes the tumor immune microenvironment, and the host anti-tumor effect depends on cyclin D3/CDK6-expressing CD8+ and CD4+ T cells. This occurs by CDK6 phosphorylating and increasing the activities of PTP1B and T cell protein tyrosine Phosphatase (TCPTP), which, in turn, decreases tyrosine phosphorylation of CD3ζ, reducing the signal transduction for T cell activation. Administration of a PTP1B and TCPTP inhibitor prove more efficacious than using a CDK6 Degrader in enhancing T cell-mediated immunotherapy. Targeting Protein tyrosine phosphatases (PTPs) might be an effective strategy for Cancer patients who resist immunotherapy treatment.

Keywords

CD3ζ; CDK6; CP: Cancer; CP: Immunology; PTP1B; TCPTP; cyclin D3.

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