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Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.

Authors :
Gubin MM
Zhang X
Schuster H
Caron E
Ward JP
Noguchi T
Ivanova Y
Hundal J
Arthur CD
Krebber WJ
Mulder GE
Toebes M
Vesely MD
Lam SS
Korman AJ
Allison JP
Freeman GJ
Sharpe AH
Pearce EL
Schumacher TN
Aebersold R
Rammensee HG
Melief CJ
Mardis ER
Gillanders WE
Artyomov MN
Schreiber RD
Source :
Nature [Nature] 2014 Nov 27; Vol. 515 (7528), pp. 577-81.
Publication Year :
2014

Abstract

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, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. 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. 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. 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.

Details

Language :
English
ISSN :
1476-4687
Volume :
515
Issue :
7528
Database :
MEDLINE
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
25428507
Full Text :
https://doi.org/10.1038/nature13988