CDK4/6 inhibitor–handled breast most cancers cells recruit T cells by way of metabolic stress-induced chemokines.
Breast most cancers is a extremely immune-evasive malignancy characterised by a low fraction of tumor-infiltrating lymphocytes (TILs) within the tumor micro-environemnt (TME). Enhancing TME T cell recruitment is significant as a result of breast most cancers sufferers with low TILs have worse survival outcomes.
Inhibitors of the cell cycle-regulating proteins CDK4/6 (CDK4/6i) are a part of combinatorial remedy for breast cancers. The authors demonstrated within the MMTV-PYMT ER+/PR+/HER2- murine mammary carcinoma mannequin that the CDK4/6i palbociclib inhibited proliferation of tumor cells, slowed tumor progress in vivo, and elevated ranges of the activation marker CD69 on CD8+ TILs. CDK4/6i additionally considerably elevated the CD8/Treg ratio within the TME. Combining palbociclib with OX40/4-1BB co-stimulatory remedies additional lowered tumor measurement in contrast with palbociclib alone, and this salutary impact of palbociclib was misplaced when T cells have been depleted, supporting the notion that palbociclib efficacy is just not primarily based solely on tumor cell–intrinsic results but in addition a results of enhancements in TIL recruitment and/or perform.
Mouse mammary tumor cells and human breast carcinoma cell traces up-regulated CCR5 ligand CCL5 and CXCR3 ligand CXCL9 mRNA and protein in vitro upon palbociclib remedy. CDK4/6i blocks Rb1 protein phosphorylation. RB1 gene mutant cell traces didn’t up-regulate CCL5 manufacturing and have been non-responsive to CDK4/6i. CCL5 de-sensitization and CXCR3 blockade abrogated homing of adoptively transferred OT-1 T cells into tumors in mice handled with CDK4/6i. Remedy with CCR5 antagonist miravoroc and CXCR3-neutralizing antibody enhanced tumor progress, even with palbociclib remedy.
CDK4/6i can induce pro-inflammatory, tumor cell–intrinsic reactive oxygen species (ROS) by way of mTORC-mediated glycolytic and oxidative metabolism. mTORC activation enhanced glucose uptake and intracellular glutamate conversion, inflicting metabolic stress in CDK4/6i-treated cells and elevated intracellular ROS and CCL5/CXCL9 manufacturing. Conversely, the ROS scavenger N-acetylcysteine (NAC) abrogated chemokine manufacturing. mTORC inhibition abrogated CDK4/6i-induced CCR5-ligand and CXCR3-ligand secretion in vitro.
Taken collectively, the interaction between cell cycle management, metabolic stress, and chemokine manufacturing was discovered to reinforce the trafficking and localization of T cells to the tumor, offering novel insights into the complexity of TME cross-talk and offering a rationale for combining CDK4/6i with T cell–activating or adoptive cell immunotherapies.
- Copyright © 2021, American Affiliation for the Development of Science