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HLA-G: a new anti-cancer therapeutic target

​Researchers at the CEA-Jacob (Immuno-Hematology Research Unit – SRHI) have designated a new target for the immunotherapy treatment of clear cell renal cell carcinoma, aimed at patients who cannot undergo conventional immunotherapy.

Published on 24 September 2021

When a cancer develops, certain immune cells that would normally eliminate tumor cells no longer fulfill their function. They are in fact tricked by the tumor cells that express a checkpoint that blocks their activation. For example, in the case of the PD1/PDL1 checkpoint, the tumor cells express a protein (PDL1) that interacts with a receptor (PD1) present on the surface of immune cells and inactivates them.

Immunotherapy treatment of certain cancers targets the PD1/PDL1 checkpoint with anti-PD1/anti-PDL1 antibodies, which allow immune cells to be activated. However, some patients do not respond to this treatment. For this reason, researchers are interested in other immune checkpoints.

For several years, researchers at the SRHI have been studying the "major histocompatibility complex antigen" (HLA-G) involved in the maternal-fetal tolerance. This protein is expressed in a healthy individual during pregnancy, on the surface of placental cells, but it can also be expressed on the surface of certain tumor cells. Its immunosuppressive effects, triggered by its interaction with ILT2/ILT4 receptors present on the surface of immune cells, could explain the resistance to current immunotherapies. Furthermore, a previous SRHI study found that the use of an anti-HLA-G antibody in a preclinical mouse model can restore an anti-tumor response.

The scientists studied the impact of HLA-G tumor expression on tumor-infiltrating T cells in patients with clear cell renal cell carcinoma. Their work shows that lymphocytes expressing CD8 (CD8+ T cells) or CD4 (CD4+ T cells) can express the ILT2 receptor that HLA-G interacts with. Interestingly, patients with ILT2+ CD4+ T cells within the tumor have fewer such cells in the periphery, indicating a preferential accumulation of these cells in the tumor tissue. In addition, CD4+ ILT2+ T cells express cytotoxic markers usually found in cytotoxic T cells, that may be very useful to kill tumor cells. However, upon contact with the HLA-G molecule, it has been shown that these lymphocytes lose their cytolytic activity, which is restored by blocking the HLA-G/ILT2 interaction.

There is therefore a reservoir of "killer" immune cells inside the tumor that needs to be "awakened".

This study paves the way for the development of a new therapeutic alternative for the treatment of HLA-G+ tumors.

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