The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade
Open accessAbstract
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control. In vitro, treatment with abemaciclib resulted in increased activation of human T cells and upregulated expression of antigen presentation genes in MCF-7 breast cancer cells. These data collectively support the clinical investigation of the combination of abemaciclib with agents such as anti-PD-L1 that modulate T cell anti-tumor immunity.
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In several preclinical tumor models, abemaciclib-mediated CDK4/CDK6 inhibition stimulates immunity by increasing MHC class I exposure on cancer cells.
“In various preclinical tumor models, CDK4/CDK6 inhibition with abemaciclib mediates immunostimulatory effects by promoting the exposure of MHC class I molecules on the cancer cell surface (Goel et al., 2017; Schaer et al., 2018).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Schaer et al., 2018
CDK4/6 inhibitors improved the efficacy of α-PD-1 in murine models by enhancing lymphocyte infiltration and TIL activities.
“CDK4/6 inhibitors improved the efficacy of α-PD-1 in murine models by enhancing lymphocyte infiltration and TIL activities [245–248].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [247]
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“Although increased MHC-I and infiltration of CD8þ T cells (14, 21) have previously been associated with CDK4/6 inhibition alone, a report on a KRAS-mutant lung cancer mouse model treated with combination MEKi, trametinib plus palbociclib, demonstrated that these infiltrating CD8þ T cells did not bear activation marker…”
Background
- Authors
- Schaer, D. A., Beckmann, R. P., Dempsey, J. A., Huber, L., Forest, A., Amaladas, N., Li, Y., Wang, Y. C., Rasmussen, E. R., Chin, D., Capen, A., Carpenito, C., Staschke, K. A., Chung, L. A., Litchfield, L. M., Merzoug, F. F., Gong, X., Iversen, P. W., Buchanan, S., de Dios, A., Novosiadly, R. D., & Kalos, M.
- Affiliations
- Eli Lilly (United States) (US)
- Corresponding author
- Novosiadly, Ruslan D.
- Kalos, Michael
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 22
- Issue
- 11
- Pages
- 2978-2994
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2789574985
- Cited by
- 469
- References
- 36
- Citations by year
- 2026: 39 · 2025: 47 · 2024: 38 · 2023: 71 · 2022: 82 · 2021: 61 · 2020: 72 · 2019: 44 · 2018: 15
- FWCI
- 18.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- abemaciclib, CDK4/6 inhibitors, PD-L1 blockade, tumor immune microenvironment, T cell activation, T cell-mediated inflammation, immunological memory, antigen presentation, hormone receptor-positive breast cancer, combination immunotherapy, MCF-7 cells, cell cycle regulation
- MeSH terms
- Aminopyridines, Benzimidazoles, Humans, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p18, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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