30 research outputs found
HLA-G/LILRBs: A Cancer Immunotherapy Challenge.
Despite some success, many patients do not benefit from immunotherapy. New strategies to improve clinical efficacy include identification of novel immune-checkpoint (IC) targets or a combination of immunotherapy with antiangiogenic treatments. Here, we propose the therapeutic use of IC, HLA-G/LILRB, and explore its enhanced synergistic antitumor activity when combined with antiangiogenic therapies
The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma
Background: Clear cell renal cell carcinoma (ccRCC), the most aggressive renal cancer, is characterized by early lymph node metastases and bad prognosis. Most therapies targeting advanced or metastatic ccRCC are based, as first-line treatment, on the administration of the vascular endothelial growth factor (VEGF) neutralizing antibody termed Bevacizumab. Despite proven benefits, the expected results were not obtained for the majority of patients.
The possibility that an intricate interplay between angiogenesis and immune-checkpoints might exist lead us to evaluate tumor angiogenesis, by means of VEGF expression together with the immune checkpoint HLA-G/ILT4.
Methods: Tumor specimens were obtained from patients from two separate cohorts: One from “Evita Pueblo” Hospital from Berazategui, (Buenos Aires, Argentina) and the second includes patients surgically operated at the Urology Department of Saint-Louis Hospital (Paris, France) with a confirmed ccRCC diagnosis.
Immunohistochemistry was performed with specific antibodies directed against HLA-G, VEGF-A, VEGF-C, D240, CD34, ILT4 and Ca-IX. In addition, gene expression levels were measured in a cell line derived from a ccRCC patient by semi-quantitative RT-PCR.
Results: Our results show that the highly vascularized tumors of ccRCC patients express high levels of VEGF and the immune-checkpoint HLA-G. In addition, ILT4, one of the HLA-G receptors, was detected on macrophages surrounding tumor cells, suggesting the generation of an immune-tolerant microenvironment that might favor tumorigenesis. Notably, RT-qPCR analysis provided the first evidence on the transcriptional relationship between HLA-G/ILT4 and the VEGF family. Namely, in the presence of HLA-G or ILT4, the levels of VEGF-A are diminished whereas those of VEGF-C are increased.
Conclusions: In an effort to find new therapeutic molecules and fight against metastasis dissemination associated with the poor survival rates of ccRCC patients, these findings provide the rationale for co-targeting angiogenesis and the immune checkpoint HLA-G.Facultad de Ciencias Médica
Genetic and Phenotypic Modifications of Hematopoietic Stem Cells in Response to Ionizing Radiation Exposure
Hematopoietic stem cells (HSC) constitute a rare population within the bone marrow (BM) which actively maintains continuous production of all mature blood cell-lineages throughout life. They are finely regulated to respond rapidly and specifically to modifications of the number of circulating cells or to environmental modifications such as radiation exposure. Although a marked sensibility to radiation exposure of these cells has been reported, little is known about the underlying mechanisms. To understand at the molecular level the cell-dependent IR response, phenotypical and transcriptional changes occurring in stem cells were monitored following exposure to total body irradiation at 2Gy, 3Gy, 6Gy, in a kinetic study from 1 hour up to 60 days. Different stem cell populations were isolated using combinations of surface molecules such as Lin-/low Sca+ C-Kit+ (LSK) with or without CD150+ and CD135+. Our results show that cells with this phenotype were completely eradicated 48h after radiation exposure. Microarray analysis showed that as early as 1 hour after radiation exposure stem cells elicit a specific damage response mostly triggered by the modulation of apoptotic genes. Many genes identified were never described before as playing a role in the IR response. Moreover, QT clustering of expression profiles and subsequent promoter analysis of co-clustered genes reveal several novel P53 co-regulated genes. The induction of these genes after radiation exposure was impaired in mutant mice deficient for P53.
Two months after 3 Gy or 6 Gy TBI, the BM cellularity was back to normal but the percentage of LSK cells was reduced and the proportion of LSK subsets expressing CD150 and/or CD135 was modified in a dose-dependant manner. Moreover, HSC presented a major defect in their long-term reconstitution potential that aroused from a blockage in their differentiation potential. This blockage can be partially abrogated by the administration of thrombopoietin. Novel actors in this signalling pathway were identified and will be presented.
These results demonstrate that irradiation, on the one hand, kill a vast majority of cycling cells in the BM by the early onset of genetic network of apoptotic genes, and on the other hand affect quiescent HSC in a cell-autonomous but reversible manner. Altogether our approach help producing a more complete knowledge of the molecular mechanisms of the stem cell radiation response by unraveling molecular networks and finding novel and specific molecules involved in this process. This information might facilitate the derivation of clinically useful targets for patient benefit