Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations
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Abstract
Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1. Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies. Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice. Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. Clin Cancer Res; 24(21); 5347–56. ©2018 AACR. See related commentary by Pawelec, p. 5193
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In 538 patients with melanoma, those over 60 years of age exhibited a better response to anti-PD-1 than those aged < 60 years.
“Kugel et al. [154] analyzed the relationship between age and anti-PD-1 response in 538 patients with melanoma and found that those over 60 years of age exhibited a better response to anti-PD-1 than those aged < 60 years.”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [154]
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- Authors
- Kugel, C. H., Douglass, S. M., Webster, M. R., Kaur, A., Liu, Q., Yin, X., Weiss, S. A., Darvishian, F., Al-Rohil, R. N., Ndoye, A., Behera, R., Alicea, G. M., Ecker, B. L., Fane, M., Allegrezza, M. J., Svoronos, N., Kumar, V., Wang, D. Y., Somasundaram, R., Hu-Lieskovan, S., Ozgun, A., Herlyn, M., Conejo-Garcia, J. R., Gabrilovich, D., Stone, E. L., Nowicki, T. S., Sosman, J., Rai, R., Carlino, M. S., Long, G. V., Marais, R., Ribas, A., Eroglu, Z., Davies, M. A., Schilling, B., Schadendorf, D., Xu, W., Amaravadi, R. K., Menzies, A. M., McQuade, J. L., Johnson, D. B., Osman, I., & Weeraratna, A. T.
- Affiliations
- The Wistar Institute (US)
- New York University (US)
- Vanderbilt-Ingram Cancer Center (US)
- 6Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California.
- 7Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, Florida.
- Moffitt Cancer Center (US)
- University of California, Los Angeles (US)
- Northwestern University (US)
- The University of Sydney (AU)
- University of Manchester (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Universitätsklinikum Würzburg (DE)
- University of Duisburg-Essen (DE)
- Hospital of the University of Pennsylvania (US)
- Corresponding author
- Weeraratna, Ashani T.
- ORCID
- Webster, Marie R.
- Kaur, Amanpreet
- Liu, Qin
- Weiss, Sarah A.
- Darvishian, Farbod
- Al-Rohil, Rami N.
- Ndoye, Abibatou
- Behera, Reeti
- Alicea, Gretchen M.
- Ecker, Brett L.
- Fane, Mitchell
- Svoronos, Nikolaos
- Wang, Daniel Y.
- Somasundaram, Rajasekharan
- Herlyn, Meenhard
- Conejo-Garcia, Jose R.
- Gabrilovich, Dmitry
- Stone, Erica L.
- Nowicki, Theodore S.
- Sosman, Jeffrey
- Carlino, Matteo S.
- Long, Georgina V.
- Marais, Richard
- Ribas, Antoni
- Eroglu, Zeynep
- Davies, Michael A.
- Schilling, Bastian
- Schadendorf, Dirk
- Xu, Wei
- Amaravadi, Ravi K.
- Menzies, Alexander M.
- McQuade, Jennifer L.
- Johnson, Douglas B.
- Osman, Iman
- Weeraratna, Ashani T.
- Venue
- Clinical Cancer Research
- Published
- 2018-11-01
- Volume
- 24
- Issue
- 21
- Pages
- 5347-5356
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC6324578
- OpenAlex
- W2808441345
- Cited by
- 367
- References
- 45
- Citations by year
- 2026: 36 · 2025: 46 · 2024: 48 · 2023: 50 · 2022: 46 · 2021: 43 · 2020: 48 · 2019: 38 · 2018: 12
- FWCI
- 13.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- NCI NIH (K23 CA204726, R01CA174746)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melanoma, anti-PD-1 therapy, immunotherapy response, patient age, regulatory T cells, CD8+ T cells, Foxp3, anti-CD25 depletion
- MeSH terms
- Antineoplastic Agents, Immunological, Age Factors, Animals, Disease Models, Animal, Female, Humans, Melanoma, Mice, Transgenic, Neoplasms, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Xenograft Model Antitumor Assays, Cell Line, Tumor, T-Lymphocytes, Regulatory, Mice, Immunomodulation, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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