A T-rojan horse strategy for cancer immunotherapy

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Science Immunology  07 May 2021:
Vol. 6, Issue 59, eabj3098
DOI: 10.1126/sciimmunol.abj3098


CDK4/6 inhibitor–treated breast cancer cells recruit T cells via metabolic stress-induced chemokines.

Breast cancer is a highly immune-evasive malignancy characterized by a low fraction of tumor-infiltrating lymphocytes (TILs) in the tumor micro-environemnt (TME). Improving TME T cell recruitment is vital because breast cancer patients with low TILs have worse survival outcomes.

Inhibitors of the cell cycle-regulating proteins CDK4/6 (CDK4/6i) are a component of combinatorial therapy for breast cancers. The authors demonstrated in the MMTV-PYMT ER+/PR+/HER2- murine mammary carcinoma model that the CDK4/6i palbociclib inhibited proliferation of tumor cells, slowed tumor growth in vivo, and elevated levels of the activation marker CD69 on CD8+ TILs. CDK4/6i also significantly increased the CD8/Treg ratio in the TME. Combining palbociclib with OX40/4-1BB co-stimulatory treatments further reduced tumor size compared with palbociclib alone, and this salutary effect of palbociclib was lost when T cells were depleted, supporting the notion that palbociclib efficacy is not based solely on tumor cell–intrinsic effects but also a result of enhancements in TIL recruitment and/or function.

Mouse mammary tumor cells and human breast carcinoma cell lines up-regulated CCR5 ligand CCL5 and CXCR3 ligand CXCL9 mRNA and protein in vitro upon palbociclib treatment. CDK4/6i blocks Rb1 protein phosphorylation. RB1 gene mutant cell lines did not up-regulate CCL5 production and were non-responsive to CDK4/6i. CCL5 de-sensitization and CXCR3 blockade abrogated homing of adoptively transferred OT-1 T cells into tumors in mice treated with CDK4/6i. Treatment with CCR5 antagonist miravoroc and CXCR3-neutralizing antibody enhanced tumor growth, even with palbociclib therapy.

CDK4/6i can induce pro-inflammatory, tumor cell–intrinsic reactive oxygen species (ROS) through mTORC-mediated glycolytic and oxidative metabolism. mTORC activation enhanced glucose uptake and intracellular glutamate conversion, causing metabolic stress in CDK4/6i-treated cells and increased intracellular ROS and CCL5/CXCL9 production. Conversely, the ROS scavenger N-acetylcysteine (NAC) abrogated chemokine production. mTORC inhibition abrogated CDK4/6i-induced CCR5-ligand and CXCR3-ligand secretion in vitro.

Taken together, the interplay between cell cycle control, metabolic stress, and chemokine production was found to enhance the trafficking and localization of T cells to the tumor, providing novel insights into the complexity of TME cross-talk and providing a rationale for combining CDK4/6i with T cell–activating or adoptive cell immunotherapies.

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