Transcriptomics,Genomics

Dataset Information

158

Checkpoint Blockade Cancer Immunotherapy Targets Tumor-Specific Mutant Antigens


ABSTRACT: Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and Programmed death-1 (PD-1) are immunoregulatory receptors expressed on T cells that play important roles in suppressing immune responses to cancer. Although monoclonal antibodies that target CTLA-4 or PD-1 stimulate therapeutic anti-tumour T cell responses, the tumour antigens recognized by checkpoint blockade immunotherapy remain undefined. Herein, we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 treatment of mice bearing progressively growing sarcomas. We validate this conclusion by showing that (a) the predicted mutant epitopes associate with MHC class I molecules of the tumour; (b) T cells specific for these mutant epitopes infiltrate tumours; and (c) therapeutic vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Whereas, T cells with the same antigen specificity are present in progressively growing tumours in control mice, tumour-specific T cells in αPD-1- and/or αCTLA-4-treated mice express some overlapping but mostly treatment-specific transcriptional profiles that render them capable of tumour rejection. Thus, tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy but also can be used to identify tumour antigen-specific T cells that function as biomarkers of successful anti-tumour responses. Overall design: For sorting of mLama4-specific cells, tumour-infiltrating cells were enriched for CD45+ cells using CD45 cell purification magnetic beads (Miltenyi Biotec). CD45 enriched cells were then sorted gating for PI- CD3ε+ CD8α+ mLama4-tetramer-PE+ or PI- CD3ε+ CD8α+ mLama4-tetramer-PE- cells. Sorting was performed on a BD FACSAria II (BD Biosciences). Sorted cells were pelleted and processed for RNA analysis. All flow cytometry was performed on the FACSCalibur (BD Biosciences) or LSR Fortessa (BD Biosciences) and analysed using FlowJo software (TreeStar).

INSTRUMENT(S): Illumina HiSeq 2500 (Mus musculus)

SUBMITTER: Maxim N. Artyomov  

PROVIDER: GSE62771 | GEO | 2014-11-07

SECONDARY ACCESSION(S): PRJNA265091

REPOSITORIES: GEO

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Publications


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  ...[more]

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