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HLA-G: a powerful immune checkpoint

Immune Checkpoints: Modulating the patient’s immune response

Immune checkpoints are safeguards mechanisms, hard-wired into immune T cells to ensure the immune system does not mistakenly target healthy cells.

When an immune checkpoint is stimulated, for example when confronted with a microbial infection, the immune response is activated and the target is attacked. When it is inhibited, for instance when interacting with a normal cell, the immune response is not triggered and the cell is left alone.
Cancer cells often neutralize these Checkpoints, thus avoiding being attacked by the immune system.

One way of assisting the patient’s immune system is to keep cancer cells from acting on these checkpoints, thereby restoring the immune response against the tumor.
This can be done by using monoclonal antibodies created to target and disable checkpoints. These antibodies, hugely important in current cancer immunotherapeutics, are known as Immune Checkpoint Inhibitors (ICI).

However, numerous studies (such as Postow et al, Frontiers in Oncology, 4, 385, 2015) show that checkpoint inhibitors are effective for fighting cancer but only in a subset of patients. Recent results on checkpoint inhibitor targets showed patient response rates between 10 and 37%. New strategies are needed to take care of the others.

HLA-G: an unexploited ICI

HLA-G is a non-classical MHC class I molecule selectively expressed at the fetal-maternal interface, protecting the fetus from the maternal immune system. Indeed, from the perspective of the mother’s immune system, the fetus is a non-self organism, and thus a target. To avoid this, HLA-G serves as a broad-range ICI which:

  • inhibits all immune cell subsets including NK, B and Antigen Presenting Cells (APC) as well as T cells
  • recruits suppressive APC and regulatory T cells inducing an immunosuppressive microenvironment for tumors.

 

In pathological conditions and particularly in cancers, HLA-G can be abnormally up-regulated, defining HLA-G as a Tumor Associated Antigen (TAA). Over 50% of cancer types express HLA-G. Its prevalence and broad action make HLA-G an exquisite antigen to target in cancer.

Invectys research has a dual purpose: providing solutions that will synergize with existing ICIs products through products such as INVAC-1 and developing novel ICI solutions targeting HLA-G, through its HLA-G Platform.