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

Autor:	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
Rok vydání:	2022
Předmět:	Cancer Research Oncology triple-negative breast cancer CDK2 cyclin E checkpoint immunotherapy PD-L1 avelumab cell cycle cyclin-dependent kinases
Zdroj:	Cancers; Volume 14; Issue 14; Pages: 3361
ISSN:	2072-6694
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::46134e088b31fc924fdfba50692c3991 https://pubmed.ncbi.nlm.nih.gov/35884422 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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