@article{99090b3d65d24783a0b3bbc92d9e8605,
title = "Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors",
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",
author = "Uzhachenko, {Roman V.} and Vijaya Bharti and Zhufeng Ouyang and Ashlyn Blevins and Stacey Mont and Nabil Saleh and Lawrence, {Hunter A.} and Chengli Shen and Chen, {Sheau Chiann} and Ayers, {Gregory D.} and DeNardo, {David G.} and Carlos Arteaga and Ann Richmond and Vilgelm, {Anna E.}",
note = "Funding Information: This work was supported by grants from BCRF ( IIDRP-16-001 to A.E.V.); NCI SPORE in Breast Cancer ( P50CA098131 ) pilot award (to A.E.V.); NIH R37 CA233770-01 (to A.E.V.); the Department of Veterans Affairs ( 5101BX000196-04 to A.R.); NIH ( CA116021 and CA116021-S1 to A.R.); and Senior Research Career Scientist Award (to A.R.). Support for core facilities used in this study was provided by VanderbiltIngram Cancer Center ( P30 CA68485 ). The Reverse Phase Protein Array (RPPA) Core at MD Anderson Cancer Center (The University of Texas) is funded by NCI CA16672 . Funding Information: This work was supported by grants from BCRF (IIDRP-16-001 to A.E.V.); NCI SPORE in Breast Cancer (P50CA098131) pilot award (to A.E.V.); NIH R37 CA233770-01 (to A.E.V.); the Department of Veterans Affairs (5101BX000196-04 to A.R.); NIH (CA116021 and CA116021-S1 to A.R.); and Senior Research Career Scientist Award (to A.R.). Support for core facilities used in this study was provided by VanderbiltIngram Cancer Center (P30 CA68485). The Reverse Phase Protein Array (RPPA) Core at MD Anderson Cancer Center (The University of Texas) is funded by NCI CA16672. R.V.U. and A.V. designed experiments. R.V.U. A.E.V. V.B. Z.O. A.B. S.M. N.S. and H.A.L. performed experiments and analyzed data. C.S. S.-C.C. and G.D.A. performed statistical analysis. C.A. and A.R. provided conceptual guidance. C.A. A.R. and D.G.D. provided models/reagents. A.V. supervised the study. R.V.U. A.V. and V.B. wrote the manuscript and prepared figures and tables. All authors reviewed and edited the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = apr,
day = "6",
doi = "10.1016/j.celrep.2021.108944",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}