Melanoma and other cancers continue to cause significant morbidity and mortality. Having discovered an immune regulator (DC-HIL) whose function can be manipulated to treat cancers, we will: (1) determine whether DC-HIL accounts for resistance to current cancer immunotherapy; (2) characterize the combination of mAb against immune targets that produces optimal treatment benefits; and (3) elucidate how blocking the DC-HIL ligand (syndecan-4) on T cells leads to better outcomes for cancer treatments. Our results will improve current management of metastatic melanoma and other cancers.
Myeloid-derived suppressor cells (MDSC) are potent T-cell repressors and their proliferation in cancer patients is a major obstacle to their successful management. Having discovered the DC-HIL receptor induced by melanoma to be expressed on MDSC and since this expression is responsible for MDSC repressor function promoting cancer growth and metastasis, we will use mouse models to address the following questions: Is resistance to the currently most effective cancer immunotherapy (anti-PD1/PDL1 mAb) due to expanded DC-HIL+ MDSC? Will blocking DC-HIL function optimize anti-PD1/PDL1 therapy? Will better understanding of T-cell activation by SD4 lead to improved anti-cancer treatment? Our outcomes will support creation of humanized anti-DC-HIL and anti-SD4 mAb that should improve treatment of metastatic melanoma and other cancers.
