CD95 receptors, also known as Fas, are called death receptors. These protein receptors reside on cell membranes. When activated, they release a signal that causes the cells to self-destruct.
Modulating Fas may also extend the benefits of chimeric antigen receptor (CAR) T-cell therapy to solid tumors like ovarian cancer.
T cells are a type of immune cells. CAR T-cell therapies involve engineering patient T cells by grafting them with a specific tumor-targeting antibody to attack tumors. These engineered T cells have shown efficacy in leukemia and other blood cancers but have failed repeatedly to provide success against solid tumors. The reason is that tumor microenvironments are good at keeping T cells and other immune cells at bay.
“These are often called cold tumors because immune cells simply cannot penetrate the microenvironments to provide a therapeutic effect,” said Tushir-Singh. “It doesn’t matter how well we engineer the immune receptor activating antibodies and T cells if they cannot get close to the tumor cells. Hence, we need to create spaces so T cells can infiltrate.”
In fact, the study showed tumors with a mutated version of the epitope of Fas receptors will not respond to CAR T at all. This finding could lead to new tests to identify which patients will benefit most from CAR T-cell immunotherapy.
Interestingly tumor cells themselves can induce CD4+ Treg-cells to produce a proliferation of CCL5 , which upregulates TGF-b (downregulated by leronlimab), inducing CD8+ T-cells to be killed through FasL. The tumor cells are protecting themselves from the CD8+ T-cells that would otherwise kill them. Not only would leronlimab stop the tumor from protecting itself but also boost killer CD8+ T-cells. Leronlimab would do what the Fas booster would do but also what the CAR-T therapy does.