Journal
NATURE IMMUNOLOGY
Volume 20, Issue 9, Pages 1231-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-019-0441-y
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Funding
- Georgia Cancer Center, Augusta University
- Ludwig Center for Cancer Immunotherapy
- National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support grant [P30 CA008748, NIH/NCI R01 CA056821]
- Swim Across America
- Ludwig Institute for Cancer Research
- Parker Institute for Cancer Immunotherapy
- Virginia B. Squiers Foundation
- Cancer Research Institute
- Adelson Medical Research Foundation
- NIH/NCI [R01CA208756]
- Lombardi Comprehensive Cancer Center support grant [P30 CA 051008]
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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(+) 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(h)(i) 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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