Between 70 and 80% of adult kidney cancers come in the form of clear cell renal cell carcinoma (ccRCC). They are prone to rapid lymph node metastases, and thus often carry a poor prognosis.

Most first-line therapies for advanced or metastatic ccRCC are based on such drugs as bevacizumab, which is an antibody that inhibits vascular endothelial growth factor A (VEGF-A). This latter participates in angiogenesis, that is, it contributes to endothelial cell migration and de novo blood vessel formation and permeability. VEGF-A inhibitors thus, in principle, block tumor-related angiogenesis, and in so doing, starve the neoplasm of the blood it needs to grow and metastasize.

Although certain angiogenesis inhibitors do provide clear benefits, they truly contribute to disease improvement for only some patients.

The last few years has also seen the development of a number of immunotherapies targeting certain proteins, such as CTLA-4 or PDL-1. Those proteins and a few others are "immune checkpoints" (ICs) that are critical for maintaining immune self tolerance and modulating immune responses to minimize tissue lesions. Tumor cells can upregulate ICs and thus protect themselves from the host's immune system.

Checkpoint inhibitors, intended to reverse the tumor-induced immunodepression, have been shown to be clinically effective for reestablishing immune function, but unfortunately only for a small number of patients. Thus, identifying new ICs or developing combinations of checkpoint inhibitors is important for improving the success rate of cancer immunotherapies.

The molecule HLA-G has been described in the literature as an IC but it has not yet been used as a therapeutic target. It was first described as a protein playing a major role in maternal-fetal immune tolerance and in tissue graft tolerance. More recently HLA-G has garnered attention because of its presence in most tumors subjected to analysis. Furthermore, it has been shown to be particularly present in ccRCC. HLA-G's immune inhibition capacity is greater than that of other ICs because it can act on most immune cells and thus block nearly all antitumor responses. ILT4 is a HLA-G receptor expressed in certain types of cancer where it contributes to tumor progression and metastasis.

To bring light to this setting, researchers from the Immuno-Hematology Research Unit (SRHI; CEA-Jacob) and the Medical Sciences Department of the National University of La Plata (Argentina) united their strengths to study angiogenesis in ccRCC samples, and more specifically correlations between VEGF expression and the HLA-G/ILT4 immune checkpoint.

Tumor samples were retrieved from two distinct cohorts comprising patients with confirmed ccRCC who underwent surgery at either the Evita Pueblo Hospital (Berazategui, Argentina) or the Urology Department of the Saint-Louis Hospital (Paris, France). The samples were subjected to immunohistochemical analyses with antibodies targeting the proteins HLA-G, VEGF-A, VEGF-C, D240, CD34, ILT4 and Ca-IX. Also, gene expression levels were measured by semiquantitative RT-PCR in a cell line derived from a patient with ccRCC.

Their results, published in BMC Cancer, showed that highly vascularized ccRCC tumors express high levels of VEGF and HLA-G. The HLA-G receptor ILT4 was detected on the macrophages surrounding the tumor cells, suggesting the creation of an immune-tolerant microenvironment that may favor tumorigenesis. 

Remarkably and unprecedentedly, the RT-PCR analysis showed that the relation between the HLA-G/ILT4 IC and the VEGF family was transcriptional, that is, operating at the gene level. Indeed, the researchers showed that in the presence of HLA-G or ILT4, levels of VEGF-A are reduced whereas those of VEGF-C are increased.

The knowledge provided by this study may enable novel ccRCC treatment protocols wherein both angiogenesis and the HLA-G/ILT4 immune checkpoint are targeted. Although the different signaling pathways involving VEGF-A and VEGF-C simultaneously remain to be determined, the development of therapies combining bevacizumab and an anti-HLA-G antibody to slow tumor growth and metastasis may represent a promising new direction to improve treatments for patients with ccRCC.