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

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 persiste...

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Published inCancer discovery Vol. 11; no. 10; pp. 2564 - 2581
Main Authors Heckler, Max, Ali, Lestat R, Clancy-Thompson, Eleanor, Qiang, Li, Ventre, Katherine S, Lenehan, Patrick, Roehle, Kevin, Luoma, Adrienne, Boelaars, Kelly, Peters, Vera, McCreary, Julia, Boschert, Tamara, Wang, Eric S, Suo, Shengbao, Marangoni, Francesco, Mempel, Thorsten R, Long, Henry W, Wucherpfennig, Kai W, Dougan, Michael, Gray, Nathanael S, Yuan, Guo-Cheng, Goel, Shom, Tolaney, Sara M, Dougan, Stephanie K
Format Journal Article
LanguageEnglish
Published United States 01.10.2021
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Summary: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 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 breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8 memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity. SIGNIFICANCE: CDK4/6 inhibition skews newly activated CD8 T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8 T-cell priming to tumor antigens prior to dosing with checkpoint blockade. .
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these authors contributed equally
ISSN:2159-8274
2159-8290
2159-8290
DOI:10.1158/2159-8290.CD-20-1540