Therefore, novel therapeutic approaches are urgently needed. 1 Advances in surgical and adjuvant treatments have only marginally improved overall survival rates since the 1970s. Without active treatment, patients with metastatic PDAC have a mean survival of 3–5 months. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumor types, with an extremely poor prognosis. Taken together, our data point to the possibility of harnessing MHC-II expression on PDAC cells for neo-antigen-based immunotherapy. 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.
Furthermore, CD4+ T-cells stimulated with neo-antigens were capable of recognizing and killing a human PDAC cell line expressing the mutated genes. 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. In fact and surprisingly, the MHC-II/LAG-3 pathway contributed to CD4+ and CD8+ T-cell cytotoxicity toward MHC-II-positive PDAC cells. 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. 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.
#Artificial academy 2 lag on windows 10 professional
MHC class II expression is a hallmark of professional antigen-presenting cells and key to the induction of CD4+ T helper cells.