van Bulow (University or college of Mainz, Germany). these genes.De novoclass II expression was observed in 26% of tumours and 42% of cell lines and may reflect the differentiation status of the cells. The high rate of class I and TAP loss has implications for immunotherapy strategies for pancreatic malignancy, as such changes could facilitate a selective growth advantage for malignant cells. However, the reinduction of expression of these molecules with cytokines such as interferon- may ultimately allow their cytotoxic T cell-mediated destruction. Keywords:antigen-presenting, malignancy, human, pancreatic == Introduction == Pancreatic adenocarcinoma affects approximately 6000 new patients in the United Kingdom each year. It is a malignancy notorious for its late stage of first presentation, aggressive clinical behaviour and its resistance to standard anti-cancer therapies [1]. Despite these characteristics, pancreatic tumours express a number of cell surface antigens which contain potential epitopes for acknowledgement by the cellular immune system. One of the mechanisms by which cancers evade the immune system in the early stage of their genesis is usually by alteration of specific molecules involved in antigen processing and presentation. Human leucocyte antigen (HLA) class I molecules are transmembrane proteins composed of two polypeptide chains: a heavy chain Rabbit Polyclonal to MAPKAPK2 and a 10-Undecenoic acid light chain (2-microglobulin). They are expressed by most nucleated cells. Their main function is to present endogenous antigenic peptides to cytotoxic T lymphocytes (CTLs). The heavy chain is usually highly polymorphic and is encoded by the closely linked loci HLA-A, -B and -C. 2-microglobulin is usually non-polymorphic and is encoded by a gene on chromosome 15. Antigen processing is necessary for the expression of class I molecules around the cell surface. Peptide fragments derived from intracellular proteins are produced by the action of the proteosome and are then transported into the endoplasmic reticulum by peptide transporter proteins such as transporter-associated protein [TAP, the product of TAP-1/TAP-2 genes located within the major histocompatibility complex (MHC) class II region around the short arm of chromosome 6] where synthesis of fully put together trimolecular HLA class I complex occurs before transport to the cell surface. Experimental deletion of TAP genes results in cells unable to present antigen in the context of class I, suggesting that this TAP gene products are an essential part of the class I complex. In a murine tumour model, loss of TAP was associated with increased tumorigenesis and growth 10-Undecenoic acid advantage compared to normal TAP-expressing counterparts [2]. However, this loss may be reversed by exogenous interferon treatment, suggesting a regulatory rather than a structural defect in TAP expression [3]. HLA class II molecules act as antigen presenters to CD4+T lymphocytes. They comprise three molecular subsets: HLA-DR, -DP and -DQ. Their expression is limited to mature cell types such as B cells, macrophages, thymocytes, dendritic cells and activated T cells. Peptides for binding to class II molecules are usually produced from extracellular antigens via the endosomal pathway. There is considerable evidence of altered MHC or HLA expression in a number of murine and human cancers [420]. Some of these studies have correlated the presence of these deficiencies with tumour progression [7,9,12,18,21]. Down-regulation or total loss of class I expression at the cell surface has been correlated with reduced expression of TAP genes in non-small cell lung, cervical, colorectal, breast and renal cell cancers and pancreatic cell lines [3,7,9,17,22,23]. Because the acknowledgement and killing of 10-Undecenoic acid tumour cells by CTLs requires the TAP proteins as well as the MHC class I molecules, it has been suggested that the loss of MHC class I and TAP expression may represent a mechanism by which these tumours escape CTL-mediated lysis. MHC class II expressionde novohas been explained in numerous cancers.De novoclass II expression has been associated with more aggressive phenotype in melanoma, whereas in breast and laryngeal carcinoma it has been associated with more benign outcome [2426]. The aim of this study was to assess the extent to which alterations of antigen processing and presentation occur in pancreatic malignancy; in particular, evaluation of HLA class I, class II and TAP expression in samples of human pancreatic malignancy and in a panel of human.