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
Affiliations
Roman V. Uzhachenko
Comprehensive Cancer Center - James, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Vijaya Bharti
Comprehensive Cancer Center - James, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Zhufeng Ouyang
Comprehensive Cancer Center - James, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Ashlyn Blevins
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA
Stacey Mont
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA
Nabil Saleh
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA
Hunter A. Lawrence
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA
Chengli Shen
Comprehensive Cancer Center - James, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Sheau-Chiann Chen
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37212, USA
Gregory D. Ayers
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37212, USA
David G. DeNardo
Department of Medicine, Washington University St. Louis, School of Medicine, St. Louis, MO 63110, USA
Carlos Arteaga
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ann Richmond
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA
Anna E. Vilgelm
Comprehensive Cancer Center - James, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Corresponding author
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.