IntroductionMesenchymal stem cells (MSCs) are important tools in treating immune disorders and in tissue repair by their multipotency, immunosuppressive properties, and production of cytokines or growth factors, Many sources of MSCs have been described and the main candidates for clinical application are bone marrow and adipocyte tissues widely available and easy to collect by standardized procedures. However, as they have in vitro and in vivo time-limited functions, 1,2 several research groups are searching for MSCs with prolonged lifetime and immunoregulatory properties. In the last decade, MSCs have been isolated from fetal or neonatal tissues [3][4][5][6][7] and embryonic tissues (ES-MSCs). [8][9][10] At present, no specific markers for the origin of the MSCs have been identified and all types of MSCs are defined by their CD105, CD90, CD73, CD44, CD29, CD146, and CD166 expression. Adult BM-MSCs exhibit immunomodulatory functions on immune cells by both cell-cell contact and soluble factors. 2,[11][12][13] Recently, human somatic cells have been successfully reprogrammed into induced pluripotent cells (iPSC) [14][15][16][17][18][19] that exhibit characteristics similar to human ES. 20 IPSC hold enormous promise for personalized cellreplacement therapy 21 and for research into various human diseases. 22,23 Therefore, MSCs derived from iPSC may be a novel source of tolerance induction, though their immunosuppressive activity remains to be explored.We report that MSCs isolated from diverse human iPS Cell lines (iPS-MSCs) can strongly inhibit the cytotoxic functions of natural killer (NK) cells. Most of these MSC-mediated inhibitory effects are because of a general impairment of NK activation and disruption of the secretory machinery on NK cells. Interestingly, iPS-MSCs and ES-MSCs are more resistant than BM-MSCs to preactivated NK cells. Our current data indicate that iPS-MSCs could represent a promising alternative strategy for the treatment of various immune-mediated diseases. Methods ReagentsThe antibodies used to assess NK and MSC phenotypes are described in supplemental Table 1 (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Recombinant human IL-2 was purchased from Immunotools, whereas Mitomycin, Monensin, and Brefaldin were purchased from Sigma-Aldrich. 1-Methyl-tryptophan (1-MT) and NS-398, specific inhibitors for Indoleamine 2,3-dioxygenase (IDO) and Prostaglandin (PGE)-2, respectively, were also purchased from Sigma-Aldrich. 87G antagonist antibody anti-HLA-G was purchased from Exbio. Pluripotent stem-cell linesWe used 3 human iPS cell lines PB3, PB10, and PB11 provided from the Stem cell Core-Facility (ES Team Paris Sud, University Paris 11, Villejuif, France) that were derived from amniotic fluid cells (AFC-iPS) after amniocentesis (Antoine Béclère Hospital, Clamart France). Their pluripotency was validated by teratoma assay, flow cytometry and RT-PCR and registered into the European Registry Web site (http://www.hescreg.eu). In addition, we de...
GJ formation occurs in vivo between T lymphocytes and tumor cells Cx43 localized at the immunological synapse between T and autologous melanoma cells Inhibition of GJs resulted in a decrease in Ag-specific CD8(+) T lymphocyte induction A role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation.
417 Background: Clear cell renal cell carcinomas frequently display inactivation of VHL gene leading to increased level of hypoxia inducible factors (HIFs). The specific role of VHL mutations and selective activation of HIF-2 alpha in modulating RCC susceptibility to cytotoxic immune response remains largely unknown. Methods: In this study, we used 786-0 RCC VHL-mutated cell line selectively induces HIF-2 alpha stabilization.Chromium release cytotoxicity assay was regularly used to evaluate tumor target cells sensitivity to NK-mediated lysis. Confocal microscopy was aso used to analyse immunologic synapse formation and for autophagy studies. Immunochemistry staining using RCC tissue microarrays was performed to evaluate HIF-2 alpha and ITPR1 expression in RCC patients. Results: We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared to the VHL-corrected cell line (WT7). This resistance was found to require HIF-2α stabilization. Based on global gene expression profiling and ChIP assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF-2α and targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Interestingly, using a large group (235) of RCC patients,we demonstrated the existence of a significant correlation between HIF-2α and ITPR1 expression Mechanistically, HIF-2α in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK mediated killing through the activation of autophagy in target cells by NK derived signal. Both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased Granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Conclusions: Our data provide insights into the link between HIF-2α, the ITPR1-related pathway and natural immunity and strongly suggest a role for the HIF-2α /ITPR1 axis in regulating RCC cell survival. Futur NK cell-based immunotherapy should integrate HIF-2/ITPR1 axis as intrinsic feature of resistance tumor cells to improve NK cell response in RCC patients.
Hypoxia is a central hallmark of tumor microenvironment and a pivotal driving force of malignant progression. Although hypoxia has been reported to play a major role in the acquisition of tumor resistance to cell death, the molecular mechanisms that enable the survival of hypoxic cancer cells have not been fully elucidated. Recently, attention has focused on the mechanisms by which hypoxic tumour cells alter their transcriptional profiles allowing them to persist under conditions of hypoxic stress. Here we demonstrate that NANOG, a transcription factor associated with stem cell self renewal, is induced under hypoxic conditions at both transcriptional and translational levels and contributes to the decreased susceptibility of target cells to specific cytotoxic T lymphocyte (CTL)-mediated lysis. The precise mechanisms by which NANOG regulates tumor susceptibility to CTL-mediated lysis will be discussed. In addition since we have demonstrated that in vivo inhibition of hypoxia restores cytotoxic T lymphocyte activity and promotes in vivo tumor regression, we will also discuss the relationship between hypoxic stress and survival pathways associated with hypoxic stress in particular the emergence of cancer stem cells and autophagy induction.
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