Journal article

Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation

Max Heckler, Lestat R Ali, Eleanor Clancy-Thompson, Li Qiang, Katherine S Ventre, Patrick Lenehan, Kevin Roehle, Adrienne Luoma, Kelly Boelaars, Vera Peters, Julia McCreary, Tamara Boschert, Eric S Wang, Shengbao Suo, Francesco Marangoni, Thorsten R Mempel, Henry W Long, Kai W Wucherpfennig, Michael Dougan, Nathanael S Gray Show all

CANCER DISCOVERY | AMER ASSOC CANCER RESEARCH | Published : 2021

Abstract

CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breas..

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Grants

Awarded by Ludwig Center at Harvard


Awarded by NIH


Awarded by Pew-Stewart Scholar in Cancer Research - Mentored Clinical Scientist Development Award


Awarded by NHMRC of Australia


Awarded by Susan G. Komen (Career Catalyst Award)


Awarded by NIH SPORE in Breast Cancer


Awarded by German Research Foundation (DFG)


Awarded by SITC-BristolMyers Squibb Postdoctoral Cancer Immunotherapy Translational Fellowship - NIH


Funding Acknowledgements

K. Dougan and N.S. Gray were funded by the Hale Center for Pancreatic Cancer Research. S.K. Dougan was funded by Eli Lilly, the Ludwig Center at Harvard, NIH U01 CA224146-01, and NIH R01 AI158488-01, and is a Pew-Stewart Scholar in Cancer Research. M. Dougan was funded by a Mentored Clinical Scientist Development Award 1K08DK114563-01. K.W. Wucherpfennig, G.-C. Yuan, M. Dougan, and S.K. Dougan were funded by the Melanoma Research Alliance and American Cancer Society. S. Goel was supported by the NHMRC of Australia (Investigator Grant GNT 1177357), Susan G. Komen (Career Catalyst Award CCR18547966), and the NIH SPORE in Breast Cancer to the Dana-Farber/Harvard Cancer Centre (P50 CA168504). M. Heckler was funded by the German Research Foundation (DFG; project number: 398222819). L. Qiang was funded by an SITC-BristolMyers Squibb Postdoctoral Cancer Immunotherapy Translational Fellowship. E. Clancy-Thompson and P. Lenehan were funded by NIH T32CA207021. P. Lenehan was funded by the Medical Scientist Training Program at Harvard. We thank Michael Manos and the DFCI Center for Immune-Oncology for sample processing. We thank the DFCI Center for Functional Cancer Epigenetics for ATAC-seq, and the DFCI Center for Cancer Immunology Research for the 10x Genomics pipeline.