posted on 2023-04-03, 23:28authored byMax 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, Guo-Cheng Yuan, Shom Goel, Sara M. Tolaney, Stephanie K. Dougan
Combined 7 supplemental figures and 1 supplemental table
Funding
Ludwig Center at Harvard
NIH
Mentored Clinical Scientist Development Award
NHMRC
Susan G. Komen
Harvard Cancer Centre
German Research Foundation
History
ARTICLE 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 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.
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.This article is highlighted in the In This Issue feature, p. 2355