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The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma.
BMC Cancer. 2020 Jul 03; 20(1):624.BC

Abstract

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.

Authors+Show Affiliations

Chair of Cytology, Histology and Embryology, Faculty of Medical Sciences, UNLP, Buenos Aires, Argentina.Chair of Cytology, Histology and Embryology, Faculty of Medical Sciences, UNLP, Buenos Aires, Argentina. LIAN, FLENI-CONICET, Escobar, Argentina.AP-HP, Saint-Louis Hospital, Department of Pathology, Paris, France. CEA, DRF-Francois Jacob Institute, Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1, avenue Claude Vellefaux, 75010, Paris, France.Chair of Cytology, Histology and Embryology, Faculty of Medical Sciences, UNLP, Buenos Aires, Argentina. LIAN, FLENI-CONICET, Escobar, Argentina.Chair of Cytology, Histology and Embryology, Faculty of Medical Sciences, UNLP, Buenos Aires, Argentina. CIC, Pcia, de Buenos Aires, Argentina.Chair of Cytology, Histology and Embryology, Faculty of Medical Sciences, UNLP, Buenos Aires, Argentina.CEA, DRF-Francois Jacob Institute, Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1, avenue Claude Vellefaux, 75010, Paris, France. AP-HP, Department of Urology, Saint-Louis Hospital, Paris, France.CEA, DRF-Francois Jacob Institute, Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1, avenue Claude Vellefaux, 75010, Paris, France. University of Paris, IRSL, UMRS 976, Paris, France.CEA, DRF-Francois Jacob Institute, Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1, avenue Claude Vellefaux, 75010, Paris, France. diana.le-roux@cea.fr. University of Paris, IRSL, UMRS 976, Paris, France. diana.le-roux@cea.fr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32620162

Citation

García, Marcela, et al. "The Immune-checkpoint HLA-G/ILT4 Is Involved in the Regulation of VEGF Expression in Clear Cell Renal Cell Carcinoma." BMC Cancer, vol. 20, no. 1, 2020, p. 624.
García M, Palma MB, Verine J, et al. The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma. BMC Cancer. 2020;20(1):624.
García, M., Palma, M. B., Verine, J., Miriuka, S., Inda, A. M., Errecalde, A. L., Desgrandchamps, F., Carosella, E. D., & Tronik-Le Roux, D. (2020). The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma. BMC Cancer, 20(1), 624. https://doi.org/10.1186/s12885-020-07113-8
García M, et al. The Immune-checkpoint HLA-G/ILT4 Is Involved in the Regulation of VEGF Expression in Clear Cell Renal Cell Carcinoma. BMC Cancer. 2020 Jul 3;20(1):624. PubMed PMID: 32620162.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma. AU - García,Marcela, AU - Palma,Maria Belen, AU - Verine,Jerome, AU - Miriuka,Santiago, AU - Inda,Ana M, AU - Errecalde,Ana L, AU - Desgrandchamps,François, AU - Carosella,Edgardo D, AU - Tronik-Le Roux,Diana, Y1 - 2020/07/03/ PY - 2019/07/18/received PY - 2020/06/25/accepted PY - 2020/7/5/entrez PY - 2020/7/6/pubmed PY - 2020/7/6/medline KW - Angiogenesis KW - HLA-G KW - ILT4 KW - Immune-therapy KW - Lymphangiogenesis KW - VEGF KW - ccRCC SP - 624 EP - 624 JF - BMC cancer JO - BMC Cancer VL - 20 IS - 1 N2 - 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. SN - 1471-2407 UR - https://www.unboundmedicine.com/medline/citation/32620162/The_immune-checkpoint_HLA-G/ILT4_is_involved_in_the_regulation_of_VEGF_expression_in_clear_cell_renal_cell_carcinoma L2 - https://bmccancer.biomedcentral.com/articles/10.1186/s12885-020-07113-8 DB - PRIME DP - Unbound Medicine ER -
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