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

Abstract

<div>Abstract<p>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<sup>+</sup> T cells during early stages of activation. Mice receiving tumor-specific CD8<sup>+</sup> 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<sup>+</sup> T cells. Silencing of <i>Mxd4 or Myc</i> in mouse CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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.</p>Significance:<p>CDK4/6 inhibition skews newly activated CD8<sup>+</sup> 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<sup>+</sup> T-cell priming to tumor antigens prior to dosing with checkpoint blockade.</p><p><i>This article is highlighted in the In This Issue feature, p. 2355</i></p></div>