Identification and Targeting of Mutant Peptide Neoantigens in Cancer Immunotherapy.
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ABSTRACT:
SUBMITTER: Verdon DJ
PROVIDER: S-EPMC8391927 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AbstractImmunotherapies targeting cancer neoantigens are safe, effective, and precise. Neoantigens can be identified mainly by genomic techniques such as next-generation sequencing and high-throughput single-cell sequencing; proteomic techniques such as mass spectrometry; and bioinformatics tools based on high-throughput sequencing data, mass spectrometry data, and biological databases. Neoantigen-related therapies are widely used in clinical practice and include neoantigen vaccines, neoantigen-specific CD8+ and CD4+ T cells, and neoantigen-pulsed dendritic cells. In addition, neoantigens can be used as biomarkers to assess immunotherapy response, resistance, and prognosis. Therapies based on neoantigens are an important and promising branch of cancer immunotherapy. Unremitting efforts are needed to unravel the comprehensive role of neoantigens in anti-tumor immunity and to extend their clinical application. This review aimed to summarize the progress in neoantigen research and to discuss its opportunities and challenges in precision cancer immunotherapy.
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Project description:Mutation-derived neoantigens distinguish tumor from normal cells. T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them. Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted toward neoantigens. Neoantigen vaccines act through antigen-presenting cells, such as dendritic cells, to activate patient-endogenous T cells that recognize vaccine-encoded mutations. Infusion of mutation-targeting T cells by adoptive cell therapy (ACT) directly increases the number and frequency of cytotoxic T cells recognizing and killing tumor cells. At the same time, publicly-funded consortia have profiled tumor genomes across many indications, identifying mutations in each tumor. For example, we find basal and HER2 positive tumors contain more mutated proteins and more TP53 mutations than luminal A/B breast tumors. HPV negative tumors have more mutated proteins than HPV positive head and neck tumors and in agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have TP53 mutations vs. 86% of the HPV negative tumors. Lung adenocarcinomas in smokers have over four times more mutated proteins relative to those in never smokers (median 248 vs. 61, respectively). With an eye toward immunotherapy applications, we review the spectrum of mutations in multiple indications, show variations in indication sub-types, and examine intra- and inter-indication prevalence of re-occurring mutation neoantigens that could be used for warehouse vaccines and ACT.
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Project description:Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programed cell death protein 1 (PD-1) or its ligand PD-L1 have increased the survival and cure rates for patients with many cancer types in various disease settings. However, only 10-40% of cancer patients benefited from these ICIs, of whom ~ 20% have treatment interruption or discontinuation due to immune-related adverse events that can be severe and even fatal. Current efforts in precision immunotherapy are focused on improving biomarker-based patient selection for currently available ICIs and exploring rationale combination and novel strategies to expand the benefit of immunotherapy to more cancer patients. Neoantigens arise from ~ 10% of the non-synonymous somatic mutations in cancer cells, are important targets of T cell-mediated anti-tumor immunity for individual patients. Advances in next generation sequencing technology and computational bioinformatics have enable the identification of genomic alterations, putative neoantigens, and gene expression profiling in individual tumors for personal oncology in a rapid and cost-effective way. Among the genomic biomarkers, defective mismatch DNA repair (dMMR), microsatellite instability high (MSI-H) and high tumor mutational burden (H-TMB) have received FDA approvals for selecting patients for ICI treatment. All these biomarkers measure high neoantigen load and tumor antigenicity, supporting the current development of neoantigen-based personalized cancer vaccines for patients with high TMB tumor. Several studies have shown neoantigen vaccines are feasible, safe and have promising clinical activity in patients with high TMB tumors in both metastatic and adjuvant settings. This review summarizes the emerging data and technologies for neoantigen-based personalized immunotherapy.
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Project description:This study was aimed at investigating the mutations in colorectal cancer (CRC) for recurrent neoantigen identification. A total of 1779 samples with whole exome sequencing (WES) data were obtained from 7 published CRC cohorts. Common HLA genotypes were used to predict the probability of neoantigens at high-frequency mutants in the dataset. Based on the WES data, we not only obtained the most comprehensive CRC mutation landscape so far but also found 1550 mutations which could be identified in at least 5 patients, including KRAS G12D (8%), KRAS G12V (5.8%), PIK3CA E545K (3.5%), PIK3CA H1047R (2.5%), and BMPR2 N583Tfs?44 (2.8%). These mutations can also be recognized by multiple common HLA molecules in Chinese and TCGA cohort as potential "public" neoantigens. Many of these mutations also have high mutation rates in metastatic pan-cancers, suggesting their value as therapeutic targets in different cancer types. Overall, our analysis provides recurrent neoantigens as potential cancer immunotherapy targets.
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