Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors

Roman V. Uzhachenko, Vijaya Bharti, Zhufeng Ouyang, Ashlyn Blevins, Stacey Mont, Nabil Saleh, Hunter A. Lawrence, Chengli Shen, Sheau Chiann Chen, Gregory D. Ayers, David G. DeNardo, Carlos Arteaga, Ann Richmond, Anna E. Vilgelm

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.

Original languageEnglish (US)
Article number108944
JournalCell Reports
Volume35
Issue number1
DOIs
StatePublished - Apr 6 2021

Keywords

  • CCL5
  • CDK4/6 inhibitors
  • ROS
  • adoptive cell transfer
  • anti-tumor immunity
  • cancer metabolism
  • chemokines
  • metabolic stress
  • palbociclib

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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