Abstract
BackgroundThe success of immunotherapeutics in oncology and the search for further improvements has prompted revisiting the use of cancer vaccines. In this context, knowledge of the immunogenic epitopes and the monitoring of the immune response cancer vaccines generate are essential. MUC1 has been considered one of the most important tumor associated antigen for decades.MethodsTo identify HLA-restricted MUC1 peptides we used eight human MHC class I transgenic mouse lines, together covering more than 80% of the human population. MUC1 peptides were identified by vaccinating each line with full length MUC1 coding sequences and using an IFNγ ELIspot restimulation assay. Relevant peptides were tested in a flow cytometry-based tetramer assay and for their capacity to serve as target in an in vivo killing assay.ResultsFour previously identified MUC1 peptides were confirmed and five are described here for the first time. These nine peptide-MHC combinations were further characterized. Six gave above-background tetramer staining of splenocytes from immunized animals and three peptides were induced more than 5% specific in vivo killing.ConclusionsThese data describe for the first time five new HLA class I-restricted peptides and revisit some that were previously described. They also emphasize the importance of using in vivo/ex vivo models to screen for immunogenic peptides and define the functions for individual peptide-HLA combinations.
Highlights
The success of immunotherapeutics in oncology and the search for further improvements has prompted revisiting the use of cancer vaccines
Fifteen-mer peptides must be randomly trimmed by proteases present in the medium to fit in the groove of major histocompatibility complex (MHC) class I molecules or can be presented by MHC class II molecules, thereby stimulating CD4+ T cell
Four such immune checkpoint inhibitors (ICI) antibodies, targeting two main, complementary inhibitory pathways are approved by the FDA in various indications: ipilimumab blocks the interaction between the cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and the CD80/ CD86 molecules on the antigen presenting cells (APC) while nivolumab, pembrolizumab and atesolizumab are inhibitors of the interaction between the programmed death 1 (PD-1) receptor and its ligand (PD-L1)
Summary
The success of immunotherapeutics in oncology and the search for further improvements has prompted revisiting the use of cancer vaccines. After many years of mitigated results, cancer immunotherapy approaches have spawned great enthusiasm because of their capacity to generate significant improvement in patients’ status in a number of pathologies [1] One of these advances exploits immunological checkpoints for which commercially approved molecules prevent the dampening of the immune response arising in the tumor environment. This mucin protein is highly distributed among cancers of epithelial origin and the cancer-associated post-translational modifications render it recognizable by the adaptive arm of the immune response While it has been repeatedly identified as a major tumor-associated antigen, MUC1-targeting cancer vaccines have met with limited success in terms of patients’ benefit [7,8,9,10,11]. While MUC1-specific immune responses have been seen in healthy donors, cancer patients and MUC1-vaccinated individuals by various means, to date, no correlation with the identified response and clinical outcome can be established [14, 15]
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