Cell Reports (Apr 2021)

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

Journal volume & issue
Vol. 35, no. 1
p. 108944

Abstract

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Summary: 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.

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