Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens

By M. Gubin, Xiuli Zhang, H. Schuster, E. Caron, J. Ward, T. Noguchi, Yulia Ivanova, Jasreet Hundal, C. Arthur, Willem-Jan Krebber and 17 more. Nature, 2014

1,894 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/f9e5051e97e3509c160290d27563d814433c1bab

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Citations in the corpus

Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures (2016, background): “A higher number of tumor mutations is expected to result in greater numbers of MHC binding neo-antigens, which have been proposed to drive tumor immune-infiltration and response to immunotherapy [9, 10, 13, 24–26].”
Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis (2016, positive): “Several recent clinical studies now demonstrate that T cells that recognize tumor-specific mutant antigens can be functionally rescued by checkpoint blockade (PD1, PD-L1, CTLA4) or expansion in vitro (Gubin et al., 2014; Lu et al., 2013; Rizvi et al., 2015; Robbins et al., 2013; Snyder et al., 2014;”
Metabolic competition in the tumor microenvironment is a driver of cancer progression (2015, methodology): “Although R and P tumors differ in antigenicity, tumor-specific T cells infiltrate both tumors (Gubin et al., 2014; Matsushita et al., 2012).”
Intratumoral Tcf1+PD‐1+CD8+ T Cells with Stem‐like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy (2019, positive): “Indeed, therapeutic vaccination can be as effective as checkpoint blockade in preclinical mouse models (Gubin et al., 2014).”
Designer vaccine nanodiscs for personalized cancer immunotherapy (2016, positive): “Coupled with the recent biomedical breakthroughs in neo-antigen screening and immune checkpoint blockade 33,34,39-41 , our approach may offer a powerful yet facile strategy for producing cancer vaccines designed for each patient.”
Natural killer cells in cancer biology and therapy (2020, background): “An example of such approach is immunecheckpoint blockade, with blocking of receptors or ligands that inhibit the activation of CTLs, including programmed cell death protein 1 (PD-1), its main ligand PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and lymphocyte-activation gene-3 (LAG-3), by monoclo”