Novel landscape of HLA‐G isoforms expressed in clear cell renal cell carcinoma patients

Abstract

Immune checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. Human leukocyte antigen G (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 anticancer 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 intratumor 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.

Intercellular transfer of HLA‐G: its potential in cancer immunology

“…Among them, four membrane‐bound (HLA‐G1‐HLA‐G4) and three soluble (HLA‐G5‐HLA‐G7) isoforms have been well studied . However, more novel HLA‐G isoforms and their biological functions and clinical significance remain to be uncovered as addressed in recent studies …”

“…4 However, more novel HLA-G isoforms and their biological functions and clinical significance remain to be uncovered as addressed in recent studies. 5,6 Since it was first observed on the foetalmaternal interface of extravillous cytotrophoblasts, a broader aberrant induction of HLA-G expression has been found in tissues and cells such as cancer cells, virus-infected cells and transplant grafts. 7 In addition, the functional properties of HLA-G have been extensively explored both in vitro and in vivo.…”

The Autoimmune Regulator (Aire) transactivates HLA‐G gene expression in thymic epithelial cells

“…Thus, the thymus expression of regulatory molecules represents an essential mechanism for the control of the immune responses in tissues. [33][34][35][36] The expression of HLA-G is also inducible in allografts without rejection and under many pathological conditions, such as cancer, viral infections, autoimmune and inflammatory diseases. 24,25 HLA-G is also constitutively expressed on chorionic and corneal tissues, [26][27][28] erythroid and endothelial precursors, 29 fetal liver and bone marrow mesenchymal stem cells, 30 and thymus cells.…”

The role of HLA‐G in parasitic diseases

“…Some insights on the differential regulation of expression of HLA‐G isoforms in response to stimulation with pro‐inflammatory cytokines in retinal pigment epithelium cells of the eye have been also provided . However, tissue‐specific patterns of splicing and function of the different isoforms are yet to be understood . Finally, besides this conventional alternative processing, a 3′ UTR splicing that occasionally affect the mRNA molecules that include the 14‐bp polymorphic sequence, resulting in the removal of 92 nucleotides and more stable transcripts, has also been documented …”

“…44 Additional isoforms have been recently described by RNAseq assays in clear cell renal cell carcinoma. 45 Some insights on the differential regulation of expression of HLA-G isoforms in response to stimulation with proinflammatory cytokines in retinal pigment epithelium cells of the eye have been also provided. 46 However, tissue-specific patterns of splicing and function of the different isoforms are yet to be understood.…”