Palbociclib-induced senescence upregulates the expression of IL-8 and may enhance the response to inmunotherapy

Abstract

Background: Senescence is a well characterized effect of the CDK4-6 inhibitors, and senescent cells have been described to produce inflammatory mediators as part of a "senescence associated secretory phenotype (SASP)". We hypothesized that CDK4/6 inhibitors, following cell cycle arrest and induction of senescence can increase the production of inflammatory mediators by breast cancer cells, such as IL-8, that are known to enhance the activity of anti-PD-L1 agents. Methods: Four cell lines were used in this study, the HER2+ AU565, the luminal A MCF-7and the triple negative (TN) MD-MB-231 and MD-MB-468 cell lines. Cells were treated for 5 days to determine if palbociclib induces senescence. Senescence was characterized through the expression of acidic beta-galactosidase and morphologic changes. Quantification of IL-8 mRNA was performed by RT-Q-PCR using the ABI Prism 7900HT. Results: Beta-galactosidase staining revealed a significant number of senescent cells after palbociclib treatment in AU565, MCF-7 and MD-MB231 lines, which also underwentmorphological changes characteristic of cell cycle arrest and senescence under microscopic examination. IL8 mRNA analyses revealed that palbociclib significantly induced IL8 expression in all the cell lines tested, including the triple negative MDA-MB-468, where senescence changes had not been observed. Conclusions: Palbociclib significantly upregulates the inflammatory mediator IL-8 in the four breast cancer cell lines tested, which included luminal, HER2+ and triple negative cells. Our resuls warrant further molecular characterization of the effects of palbociclib on tumor inflammatory microenvironment and analysis of the possible synergy of CDK4-6 inhibitors with anti-PD-L1 drugs in breast cancer. Legal entity responsible for the study: Pangaea Oncology. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.