Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types1,2,3,4,5. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8+ T cells (termed adaptive immune resistance)6,7. Here we show that pre-existing CD8+ T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8+ T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.
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This study was funded in part by National Institutes of Health grants K08 AI091663, Kure It Research Grant, UL1TR000124 (to P.C.T.), P01 CA168585, U54 CA119347, R01 CA170689, the Ressler Family Fund, the Dr Robert Vigen Memorial Fund, the Wesley Coyle Memorial Fund, and the Garcia-Corsini Family Fund (to A.R.), P30 CA16042 to D.A.E. A.R. was supported by a Stand Up To Cancer—Cancer Research Institute Cancer Immunology Dream Team Translational Research Grant (SU2C-AACR-DT1012). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.S. was supported as a Howard Hughes Medical Institute Medical Research Fellow. Some of the studies were funded by Merck Sharp and Dome and by Adaptive Biotechnologies. L.R. was supported by the V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research and a grant from the Spanish Society of Medical Oncology for Translational Research in Reference Centers. We acknowledge the Translational Pathology Core Laboratory for tissue sectioning and slide scanning, S. Roy, N. Kamsu-Kom, R. Guo, J. Pang, W. Li, A. Villanueva and K. Crawford for biopsy processing and clinical data, S. Hashaghan for assisting with quantitative imaging approaches, E. Penaflor for assisting in IHC assay optimization, execution and digital image generation, and B. Dogdas and S. Mehta who assisted with the proximity assay. We would like to thank S. Ebbinghaus, E. Rubin, S. P. Kang, R. L. Modlin, C. R. Taylor and C. Denny for critically reviewing the manuscript.
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Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients
Journal for ImmunoTherapy of Cancer (2019)