The plasticity of cancer antigen presentation by human leukocyte antigen (HLA) molecules is a crucial aspect of tumor immunology with profound implications for cancer immunotherapy. Leveraging immunopeptidomics, we conducted a comprehensive analysis to elucidate the dynamic landscape of HLA-bound peptides across distinct cancer types, including melanoma, triple-negative breast cancer (TNBC), diffuse intrinsic pontine glioma (DIPG), and Ewing sarcoma.
Utilizing high-throughput mass spectrometry techniques, we characterized the repertoire of HLA-bound peptides derived from cancer antigens within each malignancy. Our investigation revealed a remarkable variability in the HLA-bound peptide repertoire, indicative of diverse mechanisms underlying cancer antigen presentation. Notably, proteasomal splicing events accounted for 5-10% of peptides, shedding light on a previously overlooked avenue of peptide generation in cancer cells. Additionally, approximately 2% of peptides originated from non-coding genomic regions, suggesting the involvement of non-coding RNA in modulating the cancer immunopeptidome.
Moreover, our study unveiled the impact of the tumor microenvironment on HLA-bound peptide presentation. Specifically, inflammation-induced alterations in proteasome subunit expression were found to facilitate the expression of immunogenic neoantigens, underscoring the intricate interplay between tumor biology and immune recognition. Furthermore, we observed induction of HLA-II expression in certain tumours, highlighting another layer of complexity in tumour-immune interactions.
Overall, our immunopeptidomics analysis provides deep insights into the complex and dynamic nature of HLA-bound peptides in cancer antigen presentation across melanoma, TNBC, DIPG, and Ewing sarcoma. These findings hold significant implications for the development of tailored immunotherapeutic strategies aimed at exploiting the distinct immunopeptidomic landscapes of diverse malignancies.