2. Academic Validation
  3. Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation

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

  • Cancer Discov. 2021 Oct;11(10):2564-2581. doi: 10.1158/2159-8290.CD-20-1540.
Max Heckler # 1 2,  Lestat R Ali # 1 2,  Eleanor Clancy-Thompson 1 2,  Li Qiang 1 2,  Katherine S Ventre 1,  Patrick Lenehan 1 2,  Kevin Roehle 1 2,  Adrienne Luoma 1 2,  Kelly Boelaars 1,  Vera Peters 1,  Julia McCreary 1 3,  Tamara Boschert 1,  Eric S Wang 4,  Shengbao Suo 5,  Francesco Marangoni 6,  Thorsten R Mempel 6,  Henry W Long 7,  Kai W Wucherpfennig 1 2,  Michael Dougan 8 9,  Nathanael S Gray 4,  Guo-Cheng Yuan 5 10,  Shom Goel 11 12,  Sara M Tolaney 9 13,  Stephanie K Dougan 14 2
Affiliations

Affiliations

  • 1 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 2 Department of Immunology, Harvard Medical School, Boston, Massachusetts.
  • 3 Program in Chemical Biology, Harvard Medical School, Boston, Massachusetts.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 5 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 6 Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts.
  • 7 Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 8 Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
  • 9 Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • 10 Department of Genetics and Genomic Sciences, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 11 Peter MacCallum Cancer Centre, Melbourne, Australia.
  • 12 The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
  • 13 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 14 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts. Stephanie_dougan@dfci.harvard.edu.
  • # Contributed equally.
PMID: 33941591 DOI: 10.1158/2159-8290.CD-20-1540
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. 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.This article is highlighted in the In This Issue feature, p. 2355.

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