HLA-G is a newly discovered immune checkpoint affecting both innate and adaptive immune cells. Using antibodies, RNAseq, and RT-PCR, Roux et al. uncovered significant inter- and intra-tumoral HLA-G heterogeneity in ccRCC patients and described additional HLA-G isoforms that resulted from alternative splicing due to exon skipping or intron retention. This extensive heterogeneity suggests HLA-G is a complex immune and diagnostic target.
Immune-checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. HLA-G, a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor-infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anti-cancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in-depth, the HLA-G isoforms expressed in these tumors. We found that the expression of HLA-G is highly variable among tumors and distinct areas of the same tumor, testifying a marked inter- and intra-tumor heterogeneity. Moreover, our results generate an inventory of novel HLA-G isoforms which includes spliced forms that have an extended 5'-region and lack the transmembrane and alpha-1 domains. So far, these isoforms could not be detected by any method available and their assessment may improve the procedure by which tumors are analyzed. Collectively, our approach provides the first extensive portrait of HLA-G in ccRCC, and reveals data that should prove suitable for the tailoring of future clinical applications.
Author Info: (1) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, Fr
Author Info: (1) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France. Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France. (2) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France. Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France. (3) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France. Service d'Anatomo-Pathologie, AP-HP, Hopital Saint-Louis, Paris, France. (4) Centre d'Etudes du Polymorphisme Humain, Fondation Jean Dausset, Paris, France. (5) Centre d'Etudes du Polymorphisme Humain, Fondation Jean Dausset, Paris, France. (6) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France. Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France. (7) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France. Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France. (8) Centre d'Etudes du Polymorphisme Humain, Fondation Jean Dausset, Paris, France. Centre National de Genotypage, Institut de Genomique, CEA, Evry, France. (9) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France. Service d'Urologie, AP-HP, Hopital Saint-Louis, Paris, France. (10) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France. Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France.
