Oral Presentation 26th Annual Lorne Proteomics Symposium 2021

Multi-omics approach to identify cancer neo-antigens for immunotherapy (#11)

Harsha Gowda 1 2 3
  1. QIMR Berghofer, Brisbane, QLD, Australia
  2. Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
  3. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia

Cancer is one of the leading causes of death in the world. Recent advances in immunotherapy strategies have revolutionized cancer treatment. This is exemplified by therapeutic efficacy of immune checkpoint inhibitors in treating melanoma and lung cancers. However, most other cancer types do not show similar response to immune checkpoint inhibitors. This has prompted researchers to pursue other therapeutic avenues that can activate immune system to target cancer cells. Some of these strategies rely on T cell recognition of cancer cells based on neo-antigens presented on cell surface. This strategy requires identification of specific neo-antigens that are presented by MHC complex on the surface of cancer cells. Most cancer genome sequencing studies predict cancer neo-antigens based on somatic mutations identified in tumours. However, these approaches can result in several false positives as many coding mutations may not even be expressed in these cancers cells. We carried out whole genome, exome and transcriptome sequencing of gall bladder cancers from South Korea, India and Chile. By combining genomic and transcriptomic data, we identified coding mutations that are expressed in these tumours and predicted cancer neo-antigens from frequently mutated genes. Mutant peptides from ELF3, ERBB2 and TP53 were found to activate T-cells suggesting these peptides are potential cancer vaccine candidates. In order to characterize sequence determinants and other parameters that determine which neo-antigens are presented by MHC complex, we carried out exome, transcriptome, proteome and immunopeptidome analysis on melanoma, lung and breast cancer cell lines. We identified thousands of MHC bound peptides including several mutant peptides expressed in these cancer cell lines. Our data shows that most coding mutations observed at genomic level are not presented by MHC complex. By integrating multi-omics dataset from these cell lines, we investigated features that determine peptides that are most likely to be presented by MHC complex.