Baleeiro et al. studied the role of ectopically expressed MHC class II, found on over 75% of pancreatic ductal adenocarcinoma (PDAC) tumors and on several PDAC cell lines. In contrast to having an immune evasive role, the MHC-II/LAG3 pathway enhanced CD8+ and CD4+ cytotoxicity towards MHC-II-positive PDAC cells, but not proliferation or IFNγ production. In silico analysis from 127 PDAC tumors revealed a number of neoantigens that could be presented by patients’ HLA class II alleles and were immunogenic in vitro, suggesting that PDAC cells display functional MHC-II molecules loaded with tumor-derived peptides that could be harnessed for immunotherapy.
Contributed by Katherine Turner
ABSTRACT: MHC class II expression is a hallmark of professional antigen-presenting cells and key to the induction of CD4+ T helper cells. We found that these molecules are ectopically expressed on tumor cells in a large proportion of patients with pancreatic ductal adenocarcinoma (PDAC) and on several PDAC cell lines. In contrast to the previous reports that tumoral expression of MHC-II in melanoma enabled tumor cells to evade immunosurveillance, the expression of MHC-II on PDAC cells neither protected cancer cells from Fas-mediated cell death nor caused T-cell suppression by engagement with its ligand LAG-3 on activated T-cells. In fact and surprisingly, the MHC-II/LAG-3 pathway contributed to CD4+ and CD8+ T-cell cytotoxicity toward MHC-II-positive PDAC cells. By combining bioinformatic tools and cell-based assays, we identified a number of immunogenic neo-antigens that can be presented by the patients' HLA class II alleles. Furthermore, CD4+ T-cells stimulated with neo-antigens were capable of recognizing and killing a human PDAC cell line expressing the mutated genes. To expand this approach to a larger number of PDAC patients, we show that co-treatment with IFN-γ and/or MEK/HDAC inhibitors induced tumoral MHC-II expression on MHC-II-negative tumors that are IFN-γ-resistant. Taken together, our data point to the possibility of harnessing MHC-II expression on PDAC cells for neo-antigen-based immunotherapy.