Immunotherapy Screening – GITR:GITRL pathway

Activators, inhibitors and small molecules screening and enzyme profiling

In previous blogs, I invited you to read about the relevance of the B7-1 : CD28, B7-1 : CTLA4, the BLTA:HVEM, CD47:SIRPα , and the  PD-1/PD-L1/PD-L2 pathway for immunotherapy screenings and discussed the products available to work on these pathways. Today, let’s focus on the GITR:GITRL pathway (glucocorticoid-induced tumor-necrosis-factor-receptor-related protein).

The GITR:GITRL pathway is a very important target for immunotherapy drug discovery — in fact, the National Cancer Institute (USA) identified GITR modulation as one of the top 25 most promising research areas! GITR is expressed on most immune cells, including T-cells, B-cells, macrophages, and NK cells. Binding of GITR by the GITR ligand (found on antigen-presenting cells and many tumors) activates the immune response by stimulating macrophages and triggering T-cells to expand, proliferate, and differentiate. Using anti-GITR mAb to trigger GITR signaling is effective in treating viral, bacterial, and parasitic infections, as well in boosting immune response against tumors. Not surprisingly, clinical trials testing anti-GITR mAb in melanoma patients are already in progress (1).GITR - GITRL Figure

Of course, it’s never that simple. Stimulating GITR signaling in NK cells has the opposite effect compared to T-cells and macrophages—GITR signaling inhibits NK cell activity (2). Likewise, stimulation of T-suppressor cells by GITR signaling also down-regulates the immune response.   Researchers are using this to their advantage; down-regulation of the immune response can be used to treat autoimmune and inflammatory diseases, including arthritis, allergy, inflammatory bowel diseases, and graft rejection. Therefore, GITR-Fc fusion protein and mAb that block GITR signaling instead of stimulating the pathway are also being studied as potential drug candidates.

BPS Biosciences recently released a set of products linked to immunotherapeutically relevant targets, amongst them the human glucocorticoid-induced TNF-related ligand (GITRL), also known as AITRL, CD357L, or tumor necrosis factor ligand superfamily member 18 (TNFSF18).

If you are interested in this specific ligand or any other of the topics and reagents covered in previous blogs (there are links to them at the beginning of this post), don’t hesitate to get in touch (you can use the form below).

References:

(1) Nocentini, G., et al., Br J Pharmacol. 165(7): 2089-99 (2012)

(2) Barao, I., Front Immunol. 3: 402 (2012)

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Written by Ali El Baya, PhD
Ali el Bayâ is the Sales Manager at tebu-bio for the North of Europe.