Connecting the dots: therapy-induced senescence and a tumor-suppressive immune microenvironment
Open accessAbstract
BACKGROUND: Tumor cell senescence is a common outcome of anticancer therapy. Here we investigated how therapy-induced senescence (TIS) affects tumor-infiltrating leukocytes (TILs) and the efficacy of immunotherapy in melanoma. METHODS: Tumor senescence was induced by AURKA or CDK4/6 inhibitors (AURKAi, CDK4/6i). Transcriptomes of six mouse tumors with differential response to AURKAi were analyzed by RNA sequencing, and TILs were characterized by flow cytometry. Chemokine RNA and protein expression were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Therapeutic response was queried in immunodeficient mice, in mice with CCL5-deficient tumors, and in mice cotreated with CD137 agonist to activate TILs. CCL5 expression in reference to TIS and markers of TILs was studied in human melanoma tumors using patient-derived xenografts (n = 3 patients, n = 3 mice each), in AURKAi clinical trial samples (n = 3 patients, before/after therapy), and in The Cancer Genome Atlas (n = 278). All statistical tests were two-sided. RESULTS: AURKAi response was associated with induction of the immune transcriptome (P = 3.5 x 10-29) while resistance inversely correlated with TIL numbers (Spearman r = -0.87, P < .001). AURKAi and CDK4/6i promoted the recruitment of TILs by inducing CCL5 secretion in melanoma cells (P ≤ .005) in an NF-κB-dependent manner. Therapeutic response to AURKAi was impaired in immunodeficient compared with immunocompetent mice (0% vs 67% tumors regressed, P = .01) and in mice bearing CCL5-deficient vs control tumors (P = .61 vs P = .02); however, AURKAi response was greatly enhanced in mice also receiving T-cell-activating immunotherapy (P < .001). In human tumors, CCL5 expression was also induced by AURKAi (P ≤ .02) and CDK4/6i (P = .01) and was associated with increased immune marker expression (P = 1.40 x 10-93). CONCLUSIONS: Senescent melanoma cells secret CCL5, which promotes recruitment of TILs. Combining TIS with immunotherapy that enhances tumor cell killing by TILs is a promising novel approach to improve melanoma outcomes.
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CDK4/CDK6 inhibitors stimulate immunity by promoting secretion of pro-inflammatory cytokines such as type III interferon and CCL5.
“CDK4/CDK6 inhibitors mediate immunostimulatory effects by favoring the secretion of pro-inflammatory cytokines such as type III interferon (Goel et al., 2017) and CC-chemokine ligand 5 (CCL5) (Vilgelm et al., 2016).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Vilgelm et al., 2016
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- Authors
- Vilgelm, A. E., Johnson, C. A., Prasad, N., Yang, J., Chen, S.-C., Ayers, G. D., Pawlikowski, J. S., Raman, D., Sosman, J. A., Kelley, M., Ecsedy, J. A., Shyr, Y., Levy, S. E., & Richmond, A.
- Affiliations
- United States Department of Veterans Affairs (US)
- ORCID
- Venue
- JNCI Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-12-30
- Volume
- 108
- Issue
- 6
- Pages
- djv406-djv406
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC4849355
- OpenAlex
- W2333987865
- Cited by
- 95
- References
- 47
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 14 · 2023: 11 · 2022: 12 · 2021: 7 · 2020: 13 · 2019: 11 · 2018: 5 · 2017: 3 · 2016: 3
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Cancer Institute National Institutes of Health (CA116021, CA90625, CA68485)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- therapy-induced senescence, tumor cell senescence, melanoma, tumor-infiltrating lymphocytes, AURKA inhibitors, CDK4/6 inhibitors, RANTES, NF-κB signaling, chemokine recruitment, immunotherapy response, immune microenvironment, patient-derived xenografts, chemoresistance, immune transcriptome
- MeSH terms
- Animals, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Humans, Immunocompetence, Immunotherapy, Lymphocyte Activation, Melanoma, Skin Neoplasms, Gene Expression Regulation, Neoplastic, Lymphocytes, Tumor-Infiltrating, Immunocompromised Host, Cellular Senescence, Chemokine CCL5, Cell Line, Tumor, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice, Tumor Necrosis Factor Receptor Superfamily, Member 9, Tumor Microenvironment, Transcriptome, Real-Time Polymerase Chain Reaction, Aurora Kinase A, Heterografts
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