Il10

IL-10 is known to be present in the tumor microenvironment (Fig. 2.3), because it may be secreted by tumor cells and by tumor-infiltrating mononuclear cells. IL-10 expression in melanoma in situ and lymphoma cells has been well established [1, 5, 17]; it is likely that other tumors also produce IL-10. Tumor-infiltrating leukocytes are also a rich source of IL-10. Specifically, plasmacytoid DC, which accumulate in tumor draining lymph nodes produce IL-10 as do myeloid suppressor cells, which accumulate in the tumor microenvironment. The presence of IL-10 in the tumor milieu is associated with the recruitment and expansion of regulatory T cells (Treg). We and others have shown that Treg in situ and after isolation from the tumor are able to secrete IL-10 [52, 53]. This feature correlates with strong suppressor function of Treg in human TIL [52]. Neutralization of IL-10 production by CD4+CD25+Foxp3+ T cells with IL-10-specific antibodies inhibits their suppressor function, indicating that Treg-derived IL-10 is a key factor in immune-mediated suppression at the tumor site [52, 53].

Evidence for down-regulatory effects of IL-10 on APM component expression in tumor cells comes from in vitro experiments with mouse lymphoma and mastocytoma

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Fig. 2.3 Multicolor immunofluorescence for expression of IL-10 and IL-10R in a representative surgically removed SCCHN lesion. Cryostat sections of the tumor tissue were stained with IL-10-(top panels) and IL-10R-(bottom panels) specific labeled antibodies. Tumor cells are cytokeratin+ (left top and bottom panels); IL-10-(top middle panel) and IL-10R-(bottom middle panel) are expressed in the tumor; the overlay shows cytokeratin+ tumor cells stained with IL-10-(right top panel) or with IL-10R-(right bottom panel) specific labeled antibodies. Tumor cell nuclei are stained with DAPI (right top and bottom panels). X400. Courtesy of Dr. M. Szczepanski

Fig. 2.3 Multicolor immunofluorescence for expression of IL-10 and IL-10R in a representative surgically removed SCCHN lesion. Cryostat sections of the tumor tissue were stained with IL-10-(top panels) and IL-10R-(bottom panels) specific labeled antibodies. Tumor cells are cytokeratin+ (left top and bottom panels); IL-10-(top middle panel) and IL-10R-(bottom middle panel) are expressed in the tumor; the overlay shows cytokeratin+ tumor cells stained with IL-10-(right top panel) or with IL-10R-(right bottom panel) specific labeled antibodies. Tumor cell nuclei are stained with DAPI (right top and bottom panels). X400. Courtesy of Dr. M. Szczepanski cell lines. Transfection of these cells with a mouse IL-10 cDNA reduced the expression level of TAP1 and TAP2 by 30-60% and 25-35%, respectively, and of MHC class I antigens by up to 90% [49]. The causal role of IL-10 in these changes is suggested by the correlation of the degree of HLA class I antigen downregulation with levels of IL-10 secreted by the cells as well as by HLA class I antigen upregulation induced by transfection of cells with IL-10 anti-sense RNA. However, the drastic HLA class I antigen downregulation at the cell surface in spite of the limited reduction in TAP subunit expression in these cells likely reflects an additional effect of IL-10 on HLA class I heavy chain, P2 m, or tapasin transcription, because in other experiments, even very low levels of TAP have been shown to support high HLA class I antigen expression [13].

In agreement with the results obtained with the mouse cell lines tested, a dose-dependent downregulation of TAP1, TAP2 and HLA class I antigens was found in a human melanoma cell line incubated with the synthetic peptide homologous to the C-terminus of human IL-10 [30]. On the other hand, treatment of primary human B lymphocytes with human IL-10 led to TAP1 downregulation, but caused no detectable change in TAP2 expression [63]. These divergent results may reflect differences in the regulation of TAP2 in normal and malignant cells. Furthermore IL-10, which downregulates multiple genes, did not cause detectable changes in LMP7 expression in human B cells. Whether IL-10 modulates the level of other APM components and whether the findings in malignant cells and primary B lymphocytes are paralleled by similar results in dendritic cells residing in the tumor microenvironment remains to be determined.

The changes in the TAP1 levels induced by IL-10 have functional implications, since the ATP-dependent transport of peptides to the ER is reduced. As a result, immature HLA class I molecules accumulate in the ER and are poorly expressed on the cell membrane. Furthermore, TAP downregulation induced by IL-10 in human and mouse cell lines is associated with their reduced recognition by MHC class I antigen restricted, tumor antigen-specific CTL. At the same time, these cells show increased susceptibility to NK cell-mediated lysis [30, 36, 40, 49]. Although the latter finding may be explained by the downregulation of classical HLA class I antigens which inhibit NK cell-mediated cytotoxicity, one might speculate that induction or upregulation of NK-cell activating ligands by IL-10 could also contribute to enhanced NK cell-mediated killing. The latter possibility as well as the effect on HLA-G expression should be explored, since IL-10 has been shown to modulate the expression of several immunologically relevant molecules.

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