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|Title:||Immunity and immunosuppression in the tumor-host interaction|
|subject:||Tumors, MHC class 1, natural processed peptides, T cells, NK cells, IFN-[gamma], IL-10, TAP|
|Publisher:||Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)|
|Description:||With the advent of new methods in molecular biology and in peptide isolation, a number of tumor-associated antigens and their epitopes have been identified and characterized. However, tumors often grow progressively evolving different mechanisms of immune escape, resulting in resistance to MHC class I-restricted tumor-specific T cells. This thesis addresses the recognition of tumor cells by both NK cells and tumor-specific, MHC class Irestricted T cells. Moreover, I describe the mechanisms by which the cytokines interleukin 10 (IL-10) and IFN-gamma (IFN-[gamma]) can modulate MHC class I expression and the recognition by tumor specific cytotoxic T cells (CTLs) and NK cells. In my attempts to study tumor specific T-cell responses I have used two model systems. In the first one, naturally processed peptides were eluted from RMA lymphoma cells and then tested for their ability to restore the sensitivity to CTLs of the processing/presentation defective mutant line RMA-S. This allowed identification of one peptide fraction carrying a tumor antigen recognized by autologous anti-RMA CTLs. Isolated fractions loaded onto RMA-S cells could be used to induce anti-tumor CTLs in vivo. In the second system, autologous CTLs were generated against methylcholanthrene (MC)-induced mouse sarcomas. These tumors are known to carry unique tumor-specific antigens, and CTLs against one specific tumor will not react against another. Tumor specificity was confirmed in TNF-[alpha] release assays, concurring with in vivo rejection tests. Peptides eluted from MC sarcomas were fractionated by rpHPLC. Only one and unique HPLC fraction from each of the three different tumor-derived peptide eluates capacitated RMA-S to induce TNF-[alpha] release by the specific CTLs. Further, these unique antigenic fractions were all H-2K b restricted. In conclusion, my data indicate that CTL responses against MC induced sarcomas focus on one MHC class I presented antigenic peptide, distinct for each tumor. The first tumor model system allowed me to dissect a novel T-cell immune escape mechanism which is based on the immunosuppresive effect of the T helper 2 cytokine IL-10. 1 showed that IL-10 converts RMA lymphoma cells to a CTL-resistant, NK-sensitive phenotype with low but peptide-inducible MHC class I expression. IL-10 is the first cytokine reported to have these effects. This finding was also confirmed in human melanoma cells when treatment with rIL-10 resulted in a dose-dependent inhibition of CTL-mediated, HLA-A2. I -restricted, tumor-specific lysis and enhanced cytotoxic activity by NK cells. When IL-10 was expressed in the RMA lymphoma this was found to inhibit TAP-dependent translocation of peptides to the endoplasmic reticulum (ER), resulting in accumulation of immature MHC-I in the ER and subsequently low levels of MHC class I at the cell surface. Furthermore I have found that constitutive IL-10 production accounts for the high NK sensitivity, low MHC-I expression and poor TAP1/2 function in the prototype NK target YAC-1. I have also determined that a T cell independent in vivo mechanisms can revert this ability of YAC-1 cells to produce IL-10, thus restoring the MHC-I expression and TAP 1/2 function of these cells. Interferons are cytokines which can enhance tumor cell expression of MHC class 1, thereby making tumors less sensitive to NK cells. In an experimental model of metastasis I used the B 16 mouse melanoma. Pre-treatment of the melanoma cells with IFN-gamma enhanced their metastatic potential and their MHC class I expression concomitantly with protecting these tumor cells from NK lysis. Thus, IL-10 is the first cytokine shown to affect TAP expression/function and thereby MHC class I expression, which results in increased sensitivity to natural killer cells and reduced/loss of sensitivity to cytotoxic T-lymphocytes. In addition, IFN-[gamma] apper to have the reversed effects on these parameters. Through an increased knowledge of the antigens expressed on tumors and of the mechanisms tumors use to evade the immune system, novel aproaches could be developed and introduced in the treatment of cancer.|
|Appears in Collections:||Dept of Microbiology, Tumor and Cell Biology|
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