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

RG Gupta, F Li, J Roszik, G Lizée - Cancer discovery, 2021 - AACR
RG Gupta, F Li, J Roszik, G Lizée
Cancer discovery, 2021AACR
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 neoantigens, 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 …
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 neoantigens, 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 originating 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.
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