Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens

Article

关键词: EXOME ANALYSIS REVEALS;    QUANTITATIVE PROTEOMICS;    T-CELLS;    PD-1;    INFLAMMATION;    RESPONSES;    EQUILIBRIUM;    PREDICTIONS;    IPILIMUMAB;    TOLERANCE;   

DOI  :  10.1038/nature13988

来源: SCIE

【 摘 要 】

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(1-6), 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(10-13). 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

【 授权许可】

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