Abstract
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+CD38hi 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+CD38hi 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+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1231-1243 |
| Number of pages | 13 |
| Journal | Nature immunology |
| Volume | 20 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2019 |
| Externally published | Yes |
Bibliographical note
Funding Information:S.N.K., S.G. and V.V. are inventors on patent application related to work on the methods for detecting and reversing immune therapy resistance and the development of PD-1+CD38+ CD8+ T cells as a predictive and therapeutic biomarker for response/ resistance to immune checkpoint blockade therapy. S.N.K. reports an honorarium from Syndax, IO Biotech, BioLine, Northwest Biotherapeutics, Advaxis, EMD Serono, GSK, UbiVac, McKinsey, AstraZeneca and Lycera. S.N.K. reports stocks or ownership interest in Advaxis, GeorgiaImmune, IO Biotech and Northwest Therapeutics. S.N.K. is a consultant for Syndax, IO Biotech, BioLine, Kahr, PDS Biotechnology, AstraZeneca, CytomX, NewLink Genetics, AratingaBio, CanImGuide and Lycera. S.N.K. is a board member for Advaxis. S.N.K. has research contracts with Syndax, IO Biotech, BioLine, AstraZeneca, MedImmune and Lycera. T.M. is a consultant for Leap Therapeutics, Immunos Therapeutics and Pfizer and co-founder of Imvaq Therapeutics. T.M. has equity in Imvaq Therapeutics. T.M. reports grants from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics and Aprea Therapeutics. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alphavirus-based vaccines, neoantigen modeling, CD40, glucocorticoid-induced TNFR-related protein (GITR), OX40, PD-1 and CTLA-4. J.W. is a consultant for Adaptive Biotechnologies, Advaxis, Amgen, Apricity, Array BioPharma, Ascentage Pharma, Astellas Pharma, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Chugai Pharmaceutical, Elucida Oncology, Eli Lilly, F Star, Genentech, Imvaq Therapeutics, Janssen, Kleo Pharmaceuticals, Linneaus, MedImmune, Merck, Neon Therapeutics, Ono Pharmaceutical, Polaris Pharma, Polynoma, PsiOxus Therapeutics, PureTech Health, Recepta Biopharma, Sellas Life Sciences, Serametrix, Surface Oncology and Syndax. J.W. reports an honorarium from Esanex and grants/research support from Bristol-Myers Squibb, MedImmune and Genentech. J.W. has equity in Potenza Therapeutics, Tizona Therapeutics, Adaptive Biotechnologies, Elucida Oncology, Imvaq Therapeutics, BeiGene, Trieza Therapeutics, Serametrix and Linneaus. J.W. is an inventor on patent applications related to work on xenogeneic DNA vaccines, alphavirus replicon particles expressing tyrosinase-related protein-2, myeloid-derived suppressor cell assay, Newcastle disease viruses for cancer therapy, genomic signature to identify responders to ipilimumab in melanoma, engineered vaccinia viruses for cancer immunotherapy, anti-CD40 agonist monoclonal antibody fused to monophosphoryl lipid A for cancer therapy, CAR+ T cells targeting differentiation antigens as means to treat cancer, anti-PD-1 antibody, anti-CTLA-4 antibodies, anti-GITR antibodies and methods of use thereof. P.W. is a consultant for Leap Therapeutics. G.M.B. reports paid lecturing from Novartis, Takeda Oncology; sponsored research agreements with Takeda Oncology; and consulting with NW Biotherapeutics. R.J.S. reports personal fees from Amgen, Merck, Genentech and Novartis; research grants from Amgen and Merck; and clinical trial support from Merck, Tesaro, Sanofi, Genentech and Novartis during the conduct of the study; and personal fees from Compugen, Replimmune, Array and Syndax outside the submitted work. J.A.W. is an inventor on a US patent application (PCT/US17/53.717) submitted by the University of Texas MD Anderson Cancer Center that covers methods to enhance immune checkpoint blockade responses by modulating the microbiome; reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune and Bristol-Myers Squibb; serves as a consultant or advisory board member for Roche/ Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Biothera Pharmaceuticals and Microbiome DX; and receives research support from GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb and Novartis. K.T.F. owns equity in Shattuck Labs, Checkmate, X4 Pharmaceuticals; consults for Novartis, Genentech, BMS, Merck, Takeda, Verastem, Checkmate, X4 Pharmaceuticals, Sanofi, Amgen, Incyte, Adaptimmune, Shattuck Labs, Arch Oncology and Apricity; and receives research support from Novartis, Genentech, Sanofi and Amgen. N.H. is a founder and science advisory board member of Neon Therapeutics. All other authors declare no competing interests.
Funding Information:
We acknowledge the Georgia Cancer Center, Augusta University internal support grant to S.N.K. We acknowledge the Lombardi Comprehensive Cancer Center support grant to the Biostatistics and Bioinformatics shared service (P30 CA 051008). We acknowledge the Ludwig Center for Cancer Immunotherapy for financial support for the Immune Monitoring Core Facility at the MSKCC. This research was funded in part through the National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support grant no. P30 CA008748, grant no. NIH/NCI R01 CA056821, the Swim Across America, Ludwig Institute for Cancer Research, Parker Institute for Cancer Immunotherapy and Virginia B. Squiers Foundation to J.W. and T.M. The research related to the human tumor samples was supported by the Cancer Research Institute (N.H.), Adelson Medical Research Foundation (N.H.) and NIH/NCI grant no. R01CA208756 (N.H.). We thank R. Ibrahim, Parker Institute for Cancer Immunotherapy, for reviewing the manuscript.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
