Activation of CD8(+) T cells contributes to antitumor effects of CDK4/6 inhibitors plus MEK inhibitors
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Abstract
Abstract Concurrent MEK and CDK4/6 inhibition shows promise in clinical trials for patients with advanced-stage mutant BRAF/NRAS solid tumors. The effects of CDK4/6 inhibitor (CDK4/6i) in combination with BRAF/MEK-targeting agents on the tumor immune microenvironment are unclear, especially in melanoma, for which immune checkpoint inhibitors are effective in approximately 50% of patients. Here, we show that patients progressing on CDK4/6i/MEK pathway inhibitor combinations exhibit T-cell exclusion. We found that MEK and CDK4/6 targeting was more effective at delaying regrowth of mutant BRAF melanoma in immunocompetent versus immune-deficient mice. Although MEK inhibitor (MEKi) treatment increased tumor immunogenicity and intratumoral recruitment of CD8+ T cells, the main effect of CDK4/6i alone and in combination with MEKi was increased expression of CD137L, a T-cell costimulatory molecule on immune cells. Depletion of CD8+ T cells or blockade of the CD137 ligand–receptor interaction reduced time to regrowth of melanomas in the context of treatment with CDK4/6i plus MEKi treatment in vivo. Together, our data outline an antitumor immune-based mechanism and show the efficacy of targeting both the MEK pathway and CDK4/6.
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CDK4/CDK6 inhibitors can avoid or reverse the detrimental effect of MEK inhibition.
“(3) CDK4/CDK6 inhibitors (Teh et al., 2020)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Teh et al., 2020
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- Authors
- Teh, J. L. F., Erkes, D. A., Cheng, P. F., Tiago, M., Wilski, N. A., Field, C. O., Chervoneva, I., Levesque, M. P., Xu, X., Dummer, R., & Aplin, A. E.
- Affiliations
- Thomas Jefferson University (US)
- University Hospital Zurich (CH)
- 2Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland.
- University of Pennsylvania (US)
- ORCID
- Venue
- Cancer Immunology Research
- Published
- 2020-09-01
- Volume
- 8
- Issue
- 9
- Pages
- 1114-1121
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC7484433
- OpenAlex
- W3041252773
- Cited by
- 22
- References
- 26
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 2
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 CA196278, R01 CA182635, CA210944, CA224070)
- NCI (CA114046, P30 CA056036)
- U.S. Department of Defense (CA170340)
- T32 Training Program in Cancer Biology (CA236736)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CDK4/6 inhibitors, MEK inhibitors, CD8+ T cells, melanoma, BRAF mutation, CD137L, T-cell exclusion, tumor immune microenvironment, antitumor immunity, combination therapy, CD8+ T cell depletion, immune checkpoint blockade
- MeSH terms
- Acrylonitrile, Aniline Compounds, Animals, Humans, Male, CD8-Positive T-Lymphocytes, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice
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