TY - JOUR
T1 - Exploiting tumor neoantigens to target cancer evolution
T2 - Current challenges and promising therapeutic approaches
AU - Gupta, Ravi G.
AU - Li, Fenge
AU - Roszik, Jason
AU - Lizée, Gregory
N1 - Funding Information:
This work was supported by the NIH Gastrointestinal SPORE grant P50-CA221707, the Adelson Medical Research Foundation, and by philanthropic contributions to The University of Texas MD Anderson Cancer Center Pancreatic and Colorectal Cancer Moon Shots Program. The authors thank Robert Somer for critical reading of the manuscript. Figures were illustrated using BioRender.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-20-1575
DO - 10.1158/2159-8290.CD-20-1575
M3 - Review article
C2 - 33722796
AN - SCOPUS:85105497414
SN - 2159-8274
VL - 11
SP - 1024
EP - 1039
JO - Cancer discovery
JF - Cancer discovery
IS - 5
ER -