Class II transactivator-induced MHC class II expression in pancreatic cancer cells leads to tumor rejection and a specific antitumor memory response.

OBJECTIVES: The loss of major histocompatibility complex (MHC) classes I and II is a well-known mechanism by which cancer cells are able to escape from immune recognition. In this study, we analyzed the expression of antigen processing and presenting molecules in 2 cell lines derived from mouse models of pancreatic ductal adenocarcinoma (PDA) and the effects of the re-expression of MHC class II on PDA rejection. METHODS: The PDA cell lines were analyzed for the expression of MHC class I, II, and antigen-processing molecules by flow cytometry or polymerase chain reaction. We generated stable PDA-MHC class II transactivator (CIITA) cells and injected them into syngeneic mice. The CD4 and CD8 T-cell role was analyzed in vitro and in vivo. RESULTS: Murine PDA cell lines were negative for MHC and antigen-processing molecules, but their expression was restored by exogenous interferon-γ. CIITA-tumor cells were rejected in 80% to 100% of injected mice, which also developed long-lasting immune memory. In vitro assays and immunohistochemical analyses revealed the recruitment of T effector cells and CD8 T cells into the tumor area. CONCLUSIONS: Overall, these data confirm that immunotherapy is a feasible therapeutic approach to recognize and target an aggressive cancer such as PDA.

Total loss of HLA class I expression on a melanoma cell line after growth in nude mice in absence of autologous antitumor immune response.

Loss of HLA class I expression on tumor cells is a frequent event as an immune escape mechanism. Seven different altered HLA phenotypes have been defined in tumors. Various molecular mechanisms have been described as responsible for HLA class I loss. HLA class I expression alterations occur successively and unpredictably during tumor progression in vivo and immunoselection has been implicated in this process. We present an experimental xenograft model in which melanoma cell line Ando-2 injected into athymic nude mice lost total surface HLA class I expression and exhibited HLA class II cell surface expression. A strong down-regulation of HLA class I expression and de novo HLA class II expression were also found when Ando-2 melanoma cells were injected into SCID-Beige mice. These phenomena were reproducible and were only observed in local growth in nude or SCID-Beige mice and not in vitro after multiple passages. HLA class I surface expression was recovered after IFN-gamma treatment, indicating regulatory defects. The mechanism implicated in loss of HLA class I molecule expression were a down-regulation of different components of antigen processing machinery and HLA class I heavy chains. These data suggest that HLA class I alterations can also occur in absence of autologous adaptive immune response. This is a good experimental in vivo model to study the relationship between tumor progression and HLA class I alterations.