Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

Autor: Lelliott EJ; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. emily.lelliott@petermac.org.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia. emily.lelliott@petermac.org., Sheppard KE; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.; Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, VIC, Australia., McArthur GA; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
Jazyk: angličtina
Zdroj: NPJ precision oncology [NPJ Precis Oncol] 2022 Apr 20; Vol. 6 (1), pp. 26. Date of Electronic Publication: 2022 Apr 20.
DOI: 10.1038/s41698-022-00273-9
Abstrakt: CDK4/6 inhibitors (CDK4/6i) were developed as a cancer therapeutic on the basis of their tumor-intrinsic cytostatic potential, but have since demonstrated profound activity as immunomodulatory agents. While currently approved to treat hormone receptor-positive breast cancer, these inhibitors are under investigation in clinical trials as treatments for a range of cancer types, including melanoma. Melanoma is a highly immunogenic cancer, and has always been situated at the forefront of cancer immunotherapy development. Recent revelations into the immunotherapeutic activity of CDK4/6i, therefore, have significant implications for the utility of these agents as melanoma therapies. In recent studies, we and others have proven the immunomodulatory effects of CDK4/6i to be multifaceted and complex. Among the most notable effects, CDK4/6 inhibition induces transcriptional reprogramming in both tumor cells and immune cells to enhance tumor cell immunogenicity, promote an immune-rich tumor microenvironment, and skew T cell differentiation into a stem-like phenotype that is more amenable to immune checkpoint inhibition. However, in some contexts, the specific immunomodulatory effects of CDK4/6i may impinge on anti-tumor immunity. For example, CDK4/6 inhibition restricts optimal T cells expansion, and when used in combination with BRAF/MEK-targeted therapies, depletes immune-potentiating myeloid subsets from the tumor microenvironment. We propose that such effects, both positive and negative, may be mitigated or exacerbated by altering the CDK4/6i dosing regimen. Here, we discuss what the most recent insights mean for clinical trial design, and propose clinical considerations and strategies that may exploit the full immunotherapeutic potential of CDK4/6 inhibitors.
(© 2022. The Author(s).)
Databáze: MEDLINE
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