Journal Article

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens

Ward, Jeffrey P., Mulder, Gwenn E., Schuster, Heiko, Mardis, Elaine R., Ivanova, Yulia, Allison, James P., Sharpe, Arlene H., Schumacher, Ton N., Pearce, Erika L., Rammensee, Hans-Georg, Caron, Etienne, Melief, Cornelis J. M., Arthur, Cora D., Vesely, Matthew D., Artyomov, Maxim N., Schreiber, Robert D., Zhang, Xiuli, Krebber, Willem-Jan, Freeman, Gordon J., Aebersold, Ruedi, Gillanders, William E., Gubin, Matthew M., Hundal, Jasreet, Lam, Samuel S. K., Korman, Alan J., Noguchi, Takuro, Toebes, Mireille

2014

Overview

A carcinogen-induced mouse tumour model is used here to show that mutant tumour-specific antigens are targets for CD8 + T-cell responses, mediating tumour regression after checkpoint blockade immunotherapy, and that these antigens can be used effectively in therapeutic vaccines; this advance potentially opens the door to personalized cancer vaccines. Targetting tumour-specific mutant antigens In many individuals, immunosuppression is mediated by T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), immunomodulatory receptors expressed on T cells. Matthew Gubin et al . use the MCA mouse sarcoma model to show that mutant tumour antigens serve as targets for CD8 + T-cell responses, mediating tumour regression after checkpoint blockade immunotherapy with anti-PD-1 and/or anti-CTLA-4. The authors demonstrate that these antigens can be used effectively in therapeutic vaccines, suggesting a possible route to personalized cancer vaccines. 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 immunogenicity 1 , 2 , 3 , 4 , 5 , 6 , but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion 1 , 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 cells 8 , 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 malignancies 10 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45 / 45/23 / 45/91 / 631/250/251/1574 / 64/60 / 82/47 / 82/58 / 82/75 / Analysis / Animals / Antibodies, Monoclonal - therapeutic use / Antigenic determinants / Antigens / Antigens, Neoplasm - genetics / Antigens, Neoplasm - immunology / Bioinformatics / Cancer / Cancer Vaccines - therapeutic use / Care and treatment / CD8-Positive T-Lymphocytes - immunology / Cell Cycle Checkpoints - immunology / Development and progression / Drug therapy / Epitopes - genetics / Health aspects / Humanities and Social Sciences / Immune system / Immunogenicity / Immunotherapy / letter / Lymphocytes / Male / Mice / multidisciplinary / Mutants / Mutation / Peptides / Sarcoma / Sarcoma - immunology / Sarcoma - therapy / Science / Tumors / Vaccines / Vaccines, Synthetic - therapeutic use