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. GrayGuo Cheng Yuan, Shom Goel, Sara M. Tolaney, Stephanie K. Dougan

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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 dur-ing early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibi-tors 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 breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precur-sors 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.

Original languageEnglish
Pages (from-to)2564-2581
Number of pages18
JournalCancer Discovery
Volume11
Issue number10
DOIs
StatePublished - Oct 2021

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