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

被引:9
|
作者
Cheung, Anthony [1 ,2 ]
Chenoweth, Alicia M. [1 ,2 ]
Quist, Jelmar [2 ]
Sow, Heng Sheng [1 ]
Malaktou, Christina [1 ]
Ferro, Riccardo [2 ]
Hoffmann, Ricarda M. [1 ]
Osborn, Gabriel [1 ]
Sachouli, Eirini [1 ]
French, Elise [1 ]
Marlow, Rebecca [2 ]
Lacy, Katie E. [1 ]
Papa, Sophie [3 ]
Grigoriadis, Anita [2 ]
Karagiannis, Sophia N. [1 ,2 ]
机构
[1] Kings Coll London, Guys Hosp, Sch Basic & Med Biosci, St Johns Inst Dermatol, London SE1 9RT, England
[2] Kings Coll London, Guys Canc Ctr, Sch Canc & Pharmaceut Sci, Breast Canc Now Res Unit, London SE1 9RT, England
[3] Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, ImmunoEngn, London SE1 9RT, England
基金
英国医学研究理事会;
关键词
triple-negative breast cancer; CDK2; cyclin E; checkpoint immunotherapy; PD-L1; avelumab; cell cycle; cyclin-dependent kinases; DEPENDENT KINASE INHIBITOR; CELL-DEATH; MOLECULAR PORTRAITS; ANTITUMOR-ACTIVITY; DOWN-REGULATION; IN-VITRO; SNS-032; PD-L1; EXPRESSION; POTENT;
D O I
10.3390/cancers14143361
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Simple Summary The cyclin E/CDK2 complex may present a promising target axis for the treatment of triple-negative breast cancers (TNBC); however, therapeutically relevant doses of CDK2 inhibitors have been associated with toxicities. Here, we report that the suboptimal dosing of the CDK 2, 7 and 9 inhibitor SNS-032 reduced the viability of TNBC cells and upregulated the checkpoint ligand PD-L1 expression in surviving cancer cells in vitro and in human orthotopic MDA-MB-231 TNBC xenografts grown in immunodeficient mice. Moreover, in immunodeficient, TNBC xenograft-bearing mice engrafted with human immune cells, SNS-032 treatment was associated with the infiltration of CD45(+) human immune cells in tumors. In these orthotopic MDA-MB-231 TNBC-bearing mice, suboptimal SNS-032 doses given sequentially ahead of dosing with the anti-PD-L1 antibody avelumab significantly restricted tumor growth compared with monotherapy. These findings suggest that surviving cancer cells following suboptimal CDK inhibitor treatment may be responsive to checkpoint immunotherapy. 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.
引用
收藏
页数:21
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