Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints
Open accessAbstract
Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
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In anti-PD-1-treated mice with lung cancer, TIM-3 (but not VISTA) was upregulated on T cells; TIM-3 was also upregulated on T cells in adenocarcinoma patients refractory to PD-1 treatment.
“Another study noted the upregulation of the inhibitory receptor TIM-3 (but not VISTA) on the surface of T cells in anti-PD-1-treated mice with lung cancer as well as TIM-3 upregulation on T cells in adenocarcinoma patients refractory to PD-1 treatment (113).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [113]
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- Authors
- Koyama, S., Akbay, E. A., Li, Y. Y., Herter-Sprie, G. S., Buczkowski, K. A., Richards, W. G., Gandhi, L., Redig, A. J., Rodig, S. J., Asahina, H., Jones, R. E., Kulkarni, M. M., Kuraguchi, M., Palakurthi, S., Fecci, P. E., Johnson, B. E., Janne, P. A., Engelman, J. A., Gangadharan, S. P., Costa, D. B., Freeman, G. J., Bueno, R., Hodi, F. S., Dranoff, G., Wong, K.-K., & Hammerman, P. S.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Duke University (US)
- Massachusetts General Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Broad Institute (US)
- Corresponding author
- Dranoff, Glenn
- Wong, Kwok-Kin
- Hammerman, Peter S.
- ORCID
- Koyama, Shohei
- Akbay, Esra A.
- Li, Yvonne Y.
- Herter-Sprie, Grit S.
- Richards, William G.
- Gandhi, Leena
- Rodig, Scott J.
- Asahina, Hajime
- Jones, Robert E.
- Palakurthi, Sangeetha
- Fecci, Peter E.
- Johnson, Bruce E.
- Janne, Pasi A.
- Engelman, Jeffrey A.
- Costa, Daniel B.
- Freeman, Gordon J.
- Bueno, Raphael
- Hodi, F. Stephen
- Dranoff, Glenn
- Wong, Kwok-Kin
- Hammerman, Peter S.
- Venue
- Nature Communications
- Published
- 2016-02-17
- Volume
- 7
- Issue
- 1
- Pages
- 10501-10501
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4757784
- OpenAlex
- W2329974159
- Cited by
- 1,580
- References
- 40
- Citations by year
- 2026: 108 · 2025: 121 · 2024: 142 · 2023: 163 · 2022: 165 · 2021: 205 · 2020: 188 · 2019: 162 · 2018: 159 · 2017: 128 · 2016: 36
- FWCI
- 87.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Damon Runyon Cancer Research Foundation
- Brigham and Women's Hospital
- Entertainment Industry Foundation
- Deutsche Forschungsgemeinschaft (HE 6897/1-1)
- Kanae Foundation for the Promotion of Medical Science
- National Institutes of Health (5r01ca205150-04, RSG 11-186, R01AI08995, CA090578, CA120964)
- Stand Up To Cancer (SU2CAACR- DT17-15)
- National Cancer Institute (R01-CA205150, R01CA166480, CA120964, RSG 11-186, CA090578, R01CA122794, R01CA195740, R01CA140594, P50CA090578, P20CA090578, R01CA195754, R01CA163896, P01CA120964)
- National Institute of Allergy and Infectious Diseases (R01AI08995)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- adaptive resistance, anti-PD-1 therapy, TIM-3, PD-L1, lung adenocarcinoma, tumor immune microenvironment, T cells
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Aged, Animals, Humans, Lung Neoplasms, Male, Middle Aged, Receptors, Virus, Mice, Adaptive Immunity, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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