Exploiting tumor neoantigens to target cancer evolution: Current challenges and promising therapeutic approaches

Ravi G. Gupta, Fenge Li, Jason Roszik, Gregory Lizée

Research output: Contribution to journalReview articlepeer-review

49 Scopus citations

Abstract

Immunotherapeutic manipulation of the antitumor immune response offers an attractive strategy to target genomic instability in cancer. A subset of tumor-specific somatic mutations can be translated into immunogenic and HLA-bound epitopes called neo-antigens, which can induce the activation of helper and cytotoxic T lymphocytes. However, cancer immunoediting and immunosuppressive mechanisms often allow tumors to evade immune recognition. Recent evidence also suggests that the tumor neoantigen landscape extends beyond epitopes origi-nating from nonsynonymous single-nucleotide variants in the coding exome. Here we review emerging approaches for identifying, prioritizing, and immunologically targeting personalized neoantigens using polyvalent cancer vaccines and T-cell receptor gene therapy. Significance: Several major challenges currently impede the clinical efficacy of neoantigen-directed immunotherapy, such as the relative infrequency of immunogenic neoantigens, suboptimal potency and priming of de novo tumor-specific T cells, and tumor cell–intrinsic and –extrinsic mechanisms of immune evasion. A deeper understanding of these biological barriers could help facilitate the development of effective and durable immunotherapy for any type of cancer, including immunologically “cold” tumors that are otherwise therapeutically resistant.

Original languageEnglish (US)
Pages (from-to)1024-1039
Number of pages16
JournalCancer discovery
Volume11
Issue number5
DOIs
StatePublished - 2021

ASJC Scopus subject areas

  • Oncology

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