The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity1,2,3,4,5,6, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion1,2,7. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells8,9. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits—including durable responses—to patients with different malignancies10,11,12,13. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.
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We are grateful to K. Murphy for the Batf3−/− mice, T. Hansen for providing MHC class I antibodies and the H-2Kb construct, D. Fremont for the human β2m construct, and the National Institutes of Health (NIH) Tetramer Core Facility for producing MHC class I tetramers. We also thank R. Ahmed and M. Hashimoto for the multiplex staining strategy used to define functional and dysfunctional T cells. We thank A. Bensimon, O. Schubert and P. Kouvonen for instrument maintenance and for technical support with the mass spectrometry measurements and R. Vanganipuram, M. Selby and J. Valle for generating and supplying anti-PD-1 and anti-CTLA-4 in endotoxin-free sterile form. We also thank K. Sheehan, P. Allen, G. Dunn and R. Chan for constructive criticisms and comments, all members of the Schreiber laboratory for discussions, and the many members of The Genome Institute at Washington University School of Medicine. We would also like to thank W. Song for his assistance with the bioinformatics approaches, P. Kvistborg for assistance with tetramer combinatorial coding, and Christopher Nelson for advice with peptide-MHC monomer purification. This work was supported by grants to R.D.S. from the National Cancer Institute (RO1 CA043059, U01 CA141541), the Cancer Research Institute and the WWWW Foundation; to R.D.S. and W.E.G. from The Siteman Cancer Center/Barnes-Jewish Hospital (Cancer Frontier Fund); to W.E.G. from Susan G. Komen for the Cure (Promise grant); to E.R.M. from the National Human Genome Research Institute; to G.J.F. from the National Institute of Health (P50 CA101942, P01 AI054456, P50 CA101942); to A.H.S. from the National Institute of Health (P50 CA101942); and to T.N.S. from the Dutch Cancer Society (Queen Wilhelmina Research Award). E.C. is supported by a Marie Curie Intra-European Fellowship within the Seventh Framework Programme of the European Community for Research. M.M.G. was supported by a postdoctoral training grant (T32 CA00954729) from the National Cancer Institute and is currently supported by a postdoctoral training grant (Irvington Postdoctoral Fellowship) from the Cancer Research Institute. Aspects of studies at Washington University were performed with assistance by the Immunomonitoring Laboratory of the Center for Human Immunology and Immunotherapy Programs and the Siteman Comprehensive Cancer Center.
Extended data figures
This file contains MS traces for each of the mutant H-2Kb d42m1-T3 epitopes tested by targeted MS.
This file contains Supplementary Tables 1-3. Supplementary Table 1 contains a complete list of d42m1-T3 H-2Kb-bound peptides identified by discovery MS. Supplementary Table 2 shows all differentially expressed genes in mLama4-tetramer-positive CD8+ TILs from mice treated with checkpoint blockade therapy compared to mLama4-tetramer-positive CD8+ TILs from control mice. Supplementary Table 3 shows differentially regulated pathways (GSEA pathway analysis) in mLama4-tetramer-positive CD8+ TILs from mice treated with checkpoint blockade therapy compared to mLama4-tetramer-positive CD8+ TILs from control mice.
About this article
Cancer Immunology, Immunotherapy (2019)