Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance

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 immunothe...

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Veröffentlicht in:Cell reports (Cambridge) Jg. 42; H. 4; S. 112314
Hauptverfasser: Gao, Xueliang, Wu, Yongxia, Chick, Joel M., Abbott, Andrea, Jiang, Baishan, Wang, David J., Comte-Walters, Susana, Johnson, Roger H., Oberholtzer, Nathaniel, Nishimura, Michael I., Gygi, Steven P., Mehta, Anand, Guttridge, Denis C., Ball, Lauren, Mehrotra, Shikhar, Sicinski, Piotr, Yu, Xue-Zhong, Wang, Haizhen
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 25.04.2023
Elsevier
Schlagworte:
CD3ζ
CDK6
CP: Cancer
CP: Immunology
cyclin D3
Cyclin D3 - metabolism
Cyclin-Dependent Kinase 4 - metabolism
Cyclin-Dependent Kinase 6 - metabolism
Humans
Immunotherapy
Neoplasms
Phosphorylation
PTP1B
Signal Transduction
TCPTP
Tumor Microenvironment
CP: Immunology
TCPTP
CDK6
PTP1B
CP: Cancer
cyclin D3
CD3ζ
ISSN:2211-1247, 2211-1247
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Zusammenfassung: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. [Display omitted] •CDK6 expression in the tumor microenvironment shapes a pro-tumor microenvironment•CDK6 activates PTP1B and TCPTP to de-phosphorylate CD3ζ and decrease T cell activity•Targeting PTPs lessens resistance to immunotherapy•Targeting PTPs may augment adoptive T cell therapy for cancer patients Using genetic and pharmaceutical approaches, Gao et al. investigate the distinct roles of CDK4 and CDK6 in the TME to regulate tumor growth and evaluate the therapeutic potential of the CDK6-PTP-CD3ζ axis in adoptive T cell therapy.
Bibliographie:ObjectType-Article-1
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AUTHOR CONTRIBUTIONS
X.G. and H.W. conceived and designed experiments. X.G., Y.W., S.C.-W., J.M.C., and H.W. performed the experiments with help from colleagues. B.J. helped with drug preparation. N.O., M.I.N., and S.M. provided CAR T cells. A.A., D.J.W., R.H.J., S.P.G., A.M., D.C.G., L.B., P.S., and X.-Z.Y. provided advisory support. X.G. and H.W. wrote the manuscript with all authors’ input. X.G. and H.W. supervised the project.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2023.112314