Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?
- Author(s)
- Lelliott, EJ; Sheppard, KE; McArthur, GA;
- Journal Title
- NPJ Precision Oncology
- Publication Type
- Review
- Abstract
- 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.
- Department(s)
- Laboratory Research
- PubMed ID
- 35444175
- Publisher's Version
- https://doi.org/10.1038/s41698-022-00273-9
- Open Access at Publisher's Site
https://doi.org/10.1038/s41698-022-00273-9- Terms of Use/Rights Notice
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Creation Date: 2025-01-17 02:00:47
Last Modified: 2025-01-17 02:02:19