Production of IFN by T cells was also shown to participate to the onset of the adaptive response (33)
Production of IFN by T cells was also shown to participate to the onset of the adaptive response (33). this regulation. A small proportion of tumor-infiltrating NK cells and T cells were found to produce IFN, suggesting a possible direct participation to the MHCI increase around the tumor cells upon tumor cell recognition. Depletion of T cells increases the tumor growth rate, confirming their anti-tumoral role in our model. Taken together, our results demonstrate thatin vivo, NK and T cells play a dual role during the early growth of MHCIlowtumor cells. In addition to controlling the growth of tumor cells, they contribute to modifying the immunogenic profile of residual tumor cells. Keywords:mice, B16 melanoma, MHC class I, NK cells, gamma delta T cells == Introduction == Cell surface expression of MHC class I molecules by tumor cells is usually thought to be an important determinant in the interplay between tumor cells and the immune system (1). When expressed around the cell surface, MHCI molecules allow antigen presentation that is required for target cell recognition by the cytotoxic T lymphocytes (CTLs). Absence of MHCI molecules can trigger the innate part of the immune system by activating cells, such as NK cells, that express inhibitory receptors (KIRs) (2). Thus, the MHCI level on tumor cells participates in determining which arm of the immune system (adaptive or innate) can interact with tumor cells. Different studies suggest that host factors are required to maintain a sustained MHCI level on AZD5597 tumors (3-5). Nevertheless, the mechanisms which regulate MHCI expressionin vivoare not clear. Our present work aims at studying the early regulation of MHCI expression on tumor cells within their microenvironment. We hypothesized that this immune system itself plays an AZD5597 important role in this process. Firstly, the tumoral microenvironment includes immune components (6,7) which participate in the dynamics of tumor cells/stroma interactions. Secondly, immune cells known to interact with tumor cells such as T, T, NKT, NK cells, macrophages and dendritic cells (8) are producers of IFN, which is one of the major external regulators of MHCI expression. AZD5597 Thirdly, we recently showed that NKT, DC and NK cells from normal non-immune spleen regulate MHCI expressionin vitroon MHClowtumor cells by a cell-cell contact-dependent, IFN-mediated mechanism (9). We took advantage of the murine melanoma B16F10 model and its fluorescent derivative B16F10-GFP (10) which express no or few MHCI molecules due to a reversible TAP2 deficiency (11). Fluorescent tumor cells were grafted in Growth Factor Reduced Matrigel matrix (12) in order to analyze both the modification of the MHCI level on tumor cells and the recruitment of immune host cells during the early actions of tumor growth. Using this model, we were able to show that this MHCI level can be rapidly upregulated on MHCIlowtumor cells when they growin vivo. In the subcutaneous graft model, MHCI regulation is usually concomitant with the early phase of immune cell recruitment to the tumor site and depends on IFN. NK and T cells are shown to be essential to Rabbit polyclonal to Chk1.Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA.May also negatively regulate cell cycle progression during unperturbed cell cycles.This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. this process. We discuss how this regulation could impact on tumor cell recognition and tumor growth or escape. == Results == == MHCI level on B16F10 MHCI unfavorable cells is usually upregulatedin vivo == MHCI expression was examined on established tumors using the fluorescent tumor cell line B16F10-GFP (10). Comparable to their parental cells, these cells express no MHCI molecules on their surfacein vitro. B16F10-GFP cells were grafted in different locations AZD5597 and recovered ten days later.Figure 1shows that tumor cells grownin vivodisplay a detectable level of MHCI molecules whatever the grafting site. The MHCI level was found to be homogeneous on cells extracted from subcutaneous tumor masses, experimental pulmonary metastases and spontaneous lymph node metastases that spread from the intradermal graft in the ear (Figure 1). In this latter model, only 24% of the cells from the primary tumor are MHCI+. It is noteworthy that spontaneous metastases found in lymph AZD5597 nodes display a very high level of.