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Uzhachenko, Roman V.; Bharti, Vijaya; Ouyang, Zhufeng; Blevins, Ashlyn; Mont, Stacey; Saleh, Nabil; Lawrence, Hunter A.; Shen, Chengli; Chen, Sheau-Chiann; Ayers, Gregory D.; DeNardo, David G.; Arteaga, Carlos; Richmond, Ann; Vilgelm, Anna E.
Cell reports, 04/2021, Letnik: 35, Številka: 1Journal Article
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. Display omitted •Breast cancer cells treated with CDK4/6 inhibitor secrete chemokines CCL5 and CXCL10•Chemokine induction is associated with deregulated mTOR, metabolic stress, and ROS•Chemokines induced by CDK4/6 inhibitor facilitate T cell infiltration into tumors•Chemokines induced by CDK4/6 inhibitor augment adoptive T cell therapy Inhibitors of cell cycle kinases CDK4/6 delay progression of metastatic breast cancer; however, they do not eliminate tumors. Uzhachenko et al. report that metabolic changes in CDK4/6 inhibitor-treated cancer cells make them vulnerable to T cell therapies. These data highlight potential utility of CDK4/6 inhibitors to overcome immunotherapy resistance.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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