CDK Inhibition Primes for Anti-PD-L1 Treatment in Triple-Negative Breast Cancer Models.

Abstract

Triple-negative breast cancers (TNBC) expressing PD-L1 qualify for checkpoint inhibitor immunotherapy. Cyclin E/CDK2 is a potential target axis in TNBC; however, small-molecule drugs at efficacious doses may be associated with toxicity, and treatment alongside immunotherapy requires investigation. We evaluated CDK inhibition at suboptimal levels and its anti-tumor and immunomodulatory effects. Transcriptomic analyses of primary breast cancers confirmed higher cyclin E/CDK2 expression in TNBC compared with non-TNBC. Out of the three CDK2-targeting inhibitors tested, the CDK 2, 7 and 9 inhibitor SNS-032 was the most potent in reducing TNBC cell viability and exerted cytotoxicity against all eight TNBC cell lines evaluated in vitro. Suboptimal SNS-032 dosing elevated cell surface PD-L1 expression in surviving TNBC cells. In mice engrafted with human immune cells and challenged with human MDA-MB-231 TNBC xenografts in mammary fat pads, suboptimal SNS-032 dosing partially restricted tumor growth, enhanced the tumor infiltration of human CD45+ immune cells and elevated cell surface PD-L1 expression in surviving cancer cells. In tumor-bearing mice engrafted with human immune cells, the anti-PD-L1 antibody avelumab, given sequentially following suboptimal SNS-032 dosing, reduced tumor growth compared with SNS-032 alone or with avelumab without prior SNS-032 priming. CDK inhibition at suboptimal doses promotes immune cell recruitment to tumors, PD-L1 expression by surviving TNBC cells and may complement immunotherapy.

• Authors: Anthony Cheung, Alicia M Chenoweth, Jelmar Quist, Heng Sheng Sow, Christina Malaktou, Riccardo Ferro, Ricarda M Hoffmann, Gabriel Osborn, Eirini Sachouli, Elise French, Rebecca Marlow, Katie E Lacy, Sophie Papa, Anita Grigoriadis, Sophia N Karagiannis
• Journal: Cancers (Cancers (Basel)) Vol. 14 Issue 14 (Jul 11 2022) ISSN: 2072-6694 [Print] Switzerland
• PMID: 35884422 (Publication Type: Journal Article)