PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance
Open accessAbstract
Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38 hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38 hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38 hi CD8+ cells that is reversed by optimal priming. PD-1+CD38 hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.
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CD38 overexpression is associated with a dysfunctional and exhausted CD8 T population in PD1 blockade-resistant cancers.
“a recent study showed that CD38 overexpression was associated with a dysfunctional and exhausted CD8 T population in PD1 blockade-resistant cancers123,124”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [123]
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References 57 · Cited by 333
- Authors
- Verma, V., Shrimali, R. K., Ahmad, S., Dai, W., Wang, H., Lu, S., Nandre, R., Gaur, P., Lopez, J., Sade-Feldman, M., Yizhak, K., Bjorgaard, S. L., Flaherty, K. T., Wargo, J. A., Boland, G. M., Sullivan, R. J., Getz, G., Hammond, S. A., Tan, M., Qi, J., Wong, P., Merghoub, T., Wolchok, J., Hacohen, N., Janik, J. E., Mkrtichyan, M., Gupta, S., & Khleif, S. N.
- Affiliations
- Augusta University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Georgetown University Medical Center (US)
- Broad Institute (US)
- Massachusetts General Hospital (US)
- Georgetown University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Khleif, Samir N.
- ORCID
- Venue
- Nature Immunology
- Published
- 2019-07-29
- Volume
- 20
- Issue
- 9
- Pages
- 1231-1243
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC7472661
- OpenAlex
- W2964993184
- Cited by
- 333
- References
- 57
- Citations by year
- 2026: 37 · 2025: 43 · 2024: 42 · 2023: 38 · 2022: 54 · 2021: 60 · 2020: 50 · 2019: 9
- FWCI
- 18.18
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-09-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA208756, R01CA056821, P30CA008748, P30CA051008, R25CA020449)
- 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
- anti-PD-1 therapy, anti-PD-1 resistance, CD8+ T cells, CD38, T cell priming, cancer immunotherapy, therapeutic vaccination, T cell receptor signaling, predictive biomarkers
- MeSH terms
- Animals, Antibodies, Female, Humans, Immunotherapy, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms, Mice, Knockout, CD8-Positive T-Lymphocytes, Drug Resistance, Neoplasm, Cancer Vaccines, Cell Line, Tumor, Mice, ADP-ribosyl Cyclase 1, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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