Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance
Xueliang Gao,
Yongxia Wu,
Joel M. Chick,
Andrea Abbott,
Baishan Jiang,
David J. Wang,
Susana Comte-Walters,
Roger H. Johnson,
Nathaniel Oberholtzer,
Michael I. Nishimura,
Steven P. Gygi,
Anand Mehta,
Denis C. Guttridge,
Lauren Ball,
Shikhar Mehrotra,
Piotr Sicinski,
Xue-Zhong Yu,
Haizhen Wang
Affiliations
Xueliang Gao
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; Corresponding author
Yongxia Wu
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
Joel M. Chick
Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA
Andrea Abbott
Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
Baishan Jiang
Department of Cancer Biology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02215, USA
David J. Wang
Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
Susana Comte-Walters
Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA
Roger H. Johnson
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Nathaniel Oberholtzer
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
Michael I. Nishimura
Department of Surgery, Loyola University Chicago, Maywood, IL 60153, USA
Steven P. Gygi
Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA
Anand Mehta
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
Denis C. Guttridge
Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
Lauren Ball
Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA
Shikhar Mehrotra
Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
Piotr Sicinski
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
Xue-Zhong Yu
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
Haizhen Wang
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; Corresponding author
Summary: 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.
