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The last two years in scientific news
News | Scientific result | Cancer | Immune system
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
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.
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
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
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.
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.
The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma I BMC Cancer
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.