Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance. Cell Rep 2023 Apr 25;42(4):112314
Date
04/01/2023Pubmed ID
37000627Pubmed Central ID
PMC10544673DOI
10.1016/j.celrep.2023.112314Scopus ID
2-s2.0-85151481968 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
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.
Author List
Gao X, Wu Y, Chick JM, Abbott A, Jiang B, Wang DJ, Comte-Walters S, Johnson RH, Oberholtzer N, Nishimura MI, Gygi SP, Mehta A, Guttridge DC, Ball L, Mehrotra S, Sicinski P, Yu XZ, Wang HAuthors
Roger H. Johnson PhD, BA Associate Professor in the Biophysics department at Medical College of WisconsinYongxia Wu PhD, MD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Cyclin D3Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Humans
Immunotherapy
Neoplasms
Phosphorylation
Signal Transduction
Tumor Microenvironment
