Tumor Necrosis Factor receptor super family members (TNFRSFs) play an important role in the immune responses and inflammatory reactions. One of TNFRSFs, TNFRSF18 (GITR), a recently identified novel tumor suppressor on chromosome 1p36, loss of which might be highly related to pathogenesis in differential human cancers. It has been reported that GITR / TNFRSF18 deficiency could result in increased cell proliferation and reduced apoptosis in human Multiple Myeloma (MM). NF-κB transcription factors play a key role in the survival and proliferation of many kinds of B-cell tumors, especially for multiple myeloma. It has also been shown that mutations involved in the NF-κB pathway are present in 15–20% of MM tumors. These mutations can lead to activation of the canonical and non-canonical NF-κB pathway. Therefore, targeting the NF-κB pathway is an attractive therapy approach for MM. In previous report, it has been shown that GITR / TNFRSF18 expression also impacts the NF-κB activation in response to GITR Ligand/TNFSF18. These findings above indicate that GITR / TNFRSF18 might also be important to drug response through modulating NF-κB pathway since NF-κB inhibitors were developed to treat MM patients in the past years.
It has also been shown that GITR & GITR Ligand immune checkpoint pathway can regulate immunity by potentiating CD4+ and CD8+ effector T cell function while modulating regulatory T cells. In tumor bearing mice, treatment with the GITR agonist monoclonal antibody mDTA-1 has been shown to increase intratumoral effector T cell function and decrease regulatory T cell stability, culminating in effective tumor regression.
Brunn ND et al. The Role of Anti-drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice. J Pharmacol Exp Ther. 2015.