Mesothelioma is a highly aggressive cancer with a median survival of rate of 12 months. Current disease burden is peaking in countries like Australia and most treatments are simply palliative. The use of immunotherapies, that have revolutionised treatment of other cancers, is still in its infancy in mesothelioma. The current study explores the HLA class I antigenic landscape of mesothelioma using a multi-omics approach in both a murine mesothelioma model, patient derived cell lines (n = 11) and patient pleural effusion (PE) samples (n = 4). Since mesothelioma is low tumour burden cancer, apart from identification of neopeptides, we also investigated for endogenous retroviruses (ERVs) in both mouse model and human samples. In patient samples we also investigated the repertoire of post translationally modified (PTM) peptides and tumour associated antigens (TAA).
In the mouse model we identified several neopeptides from mutated sequences and mouse ERV peptides from a total of 11,248 peptides. Several of the identified neopeptides were found to be immunogenic. In patient derived cell lines and PE samples we identified ~150,000 peptides in total. In our analysis we found a small number of mutated neoantigen-derived peptides but alongside we identified several peptides from TAAs of interest such as Mesothelin (MSLN), Wilms Tumour (WT) and Fibulin (FLB3) across different cell lines. Interestingly, another class of antigen was prevalent in the cell lines, these were cysteine containing HLA class I peptides. There was an abundance of peptides derived from human ERVs, in particular peptides derived from LTRs and LINEs.
In conclusion, our study highlights different categories of peptides which can be a part of immunotherapy efforts and may be of great value in the treatment of mesothelioma and related tumours.