Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance
Year: 2023
Type: article
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.
Source: Cell Reports
Authors: 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
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: Foundation for the National Institutes of Health, American Cancer Society, Bristol-Myers Squibb, Leukemia Research Foundation, Novartis Pharmaceuticals Corporation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1492243288, G1641442230, G2447991297, New Sample Multiplexing Technologies to Identify Chemical Probes and Illuminate Ubiquitin Biology, Orbitrap Fusion Lumos ETD Mass Spectrometer, G707397932, G7159966850, G732836964, G9000077801, G9000135763, G9000269983, Novel functions of CDK6 in T-cell leukemia progression, Targeting PIM-2 Kinase for Improving Cancer Immunotherapy, COBRE in Digestive and Liver Disease
OpenAlex ID: W4361266945