Identification of Mutated Peptides as Potential Neoantigen-Based Immunotherapy in Bladder Cancer - Expert Commentary

Bladder cancers (BC) are among tumor types with a high mutation load. Somatic mutations can encode mutant peptides that can be recognized by T-cells as neoantigens triggering an anti-tumor immune response. T cells can identify mutant epitopes when presented by human leukocyte antigen (HLA) class I molecules. The HLA-1 profile in a cancer patient is a crucial determinant of the immunoreactivity against cancer neoepitopes.


A recent study by Wang et al., published in Frontiers in Immunology, investigated the immunoreactivity and clinical relevance of mutated (MT) and wild-type (WT) peptides in BC patients. The study aimed to identify candidate neoantigens for further neoantigen-based immunotherapy applications for BC patients.

The investigators limited their study to 40 BC patients who expressed HLA-A2+ and were recruited from Xinhua Hospital, Shanghai, China. First, they used whole-exome sequencing data from 412 BC patients from the Cancer Genome Atlas (TCGA) to identify 920 peptides restricted to HLA-A*02:01. They selected the top 57 pairs of WT and MT peptides with HLA-A*02:01 restriction for peptide synthesis. The performed in vitro T2 cell-binding assay showed that 12 MT peptides had higher affinity than WT peptides. Second, the investigators isolated peripheral blood mononuclear cells (PBMCs) from the 40 BC patients and used the in vitro ELISPOT assay to determine immunoreactivity to WT and MT peptides. MT peptides were found to generate more peptide-specific IFNg spot-forming units (SFUs) than WT counterparts. A combination of MT peptides from 6 genes, occurring in 47.5% of patients, were associated with longer disease-free survival in the BC TCGA cohort. In addition, patients with higher C-reactive protein levels showed lower immunoreactivity to MT peptides.

The authors argue that the identified MT peptides should be further investigated as potential neoantigen candidates for cancer immunotherapy for BC patients. This approach can be used to study other commonly occurring HLA allele profiles in BC patients. The frequency of HLA class I alleles differs significantly among various ethnicities. Future personalized immunotherapeutic medicine strategies accounting for each cancer’s immunopeptidome and HLA molecules are needed.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Wang, Chen, Yu Ding, Yuanyong Liu, Qingchen Zhang, Shiqiang Xu, Liliang Xia, Huangqi Duan et al. "Identification of Mutated Peptides in Bladder Cancer From Exomic Sequencing Data Reveals Negative Correlation Between Mutation-Specific Immunoreactivity and Inflammation." Frontiers in immunology 11 (2020): 3103.
  2. Gourraud, Pierre-Antoine, Pouya Khankhanian, Nezih Cereb, Soo Young Yang, Michael Feolo, Martin Maiers, John D. Rioux, Stephen Hauser, and Jorge Oksenberg. "HLA diversity in the 1000 genomes dataset." PloS one 9, no. 7 (2014): e97282.
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