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

Cell Rep. 2021 Apr 6;35(1):108944. doi: 10.1016/j.celrep.2021.108944.

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.

Keywords: CCL5; CDK4/6 inhibitors; ROS; adoptive cell transfer; anti-tumor immunity; cancer metabolism; chemokines; metabolic stress; palbociclib.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Chemokines / metabolism*
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Female
  • Humans
  • Hypertrophy
  • Immunotherapy
  • Mammary Neoplasms, Animal / immunology*
  • Mammary Neoplasms, Animal / pathology
  • Mammary Neoplasms, Animal / therapy
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Receptors, Chemokine / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Chemokines
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • Receptors, Chemokine
  • TOR Serine-Threonine Kinases
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6