Immunotherapy is an emerging approach for untreatable cancers. One promising immunotherapy approach is peptide vaccination, which stimulates tumoricidal killer T cell responses. The fundamental basis for cancer vaccination is immune recognition of peptides exclusively presented on the tumour surface in complex with Human Leukocyte Antigen (HLA) molecules. We have recently shown that a high proportion (20-40%) of peptide-HLA complexes (p-HLA) that present on the cell surface are generated through proteasomal splicing post-transactional modification, which two parts of one or two proteins are excised and then ligated to form a novel peptide(1).
Here we studied the contribution of spliced peptides in tumour recognition different cancer cell lines including Melanoma, Diffuse-Intrinsic-Pontine-Glioma, colon-cancer carcinoma and triple-negative breast cancer. We found: First ~10-50% of peptides that derived from cancer antigens (CA) are presenting in spliced form. Second, the majority of CA-spliced peptides are shared between cell lines with the same HLA allomorph but from individual patients(2). Third, some cancer antigens are highly susceptible to splicing as >10 spliced peptides were identified from P-Mel and CDK1. Forth, some of the CA-spliced peptides were shared between distinct cancer types. Fifth, several of CA-spliced peptides were shown to be immunogenic in unrelated patients. Sixth, vaccination of mouse with some of the CA-spliced peptides significantly reduced the size of tumours. Clinical studies for vaccination of melanoma patients with some of the discovered cancer-specific spliced peptides are ongoing.
Understanding the nature and abundance of spliced peptides has high relevance for our understanding of potential novel targets of T cell immunity and will have significant implications for further immunotherapeutic approaches. Current cancer vaccination strategies are based on targeting cancer-associated mutations which are extremely personalised. Our observations show that spliced peptides play a major role in tumour antigen recognition. Splicing hotspot sites on cancer antigens are shared between distinct types of tumours. Therefore spliced peptides generated from these hotspots have potentials to be targeted for universal cancer vaccination.