Blocking monocytic myeloid-derived suppressor cell function via anti-DC-HIL/GPNMB antibody restores the in vitro integrity of T-cells from cancer patients

Purpose: Blocking the function of myeloid-derived suppressor cells (MDSCs) is an attractive approach for cancer immunotherapy. Having shown DC-HIL/GPNMB to be the T cell-inhibitory receptor mediating the suppressor function of MDSCs, we evaluated the potential of anti-DC-HIL monoclonal antibody (mAb) as a MDSC-targeting cancer treatment. Experimental Design: Metastatic cancer patients (n=198) were analyzed by flow-cytometry for DC-HIL or PDL1 expression on blood CD14+HLA-DRno/lo MDSCs. Their suppressor function was assessed by in vitro co-culture with autologous T-cells, and the ability of anti-DC-HIL or anti-PDL1 mAb to reverse such function was determined. Tumor expression of these receptors was examined histologically, and the anti-tumor activity of the mAb was evaluated by attenuated growth of colon cancers in mice. Results: Metastatic cancer patients had high blood levels of DC-HIL+ MDSCs compared to healthy controls. Anti-DC-HIL mAb reversed the in vitro function in ~80% of cancer patients tested, particularly for colon cancer. Despite very low expression on blood MDSCs, anti-PDL1 mAb was as effective as anti-DC-HIL mAb in reversing MDSC function, a paradoxical phenomenon we found to be due to upregulated expression of PDL1 by T cell-derived IFN-Υ in co-cultures. DC-HIL is not expressed by colorectal cancer cells, but by CD14+ cells infiltrating the tumor. Finally, anti-DC-HIL mAb attenuated growth of pre-established colon tumors by reducing MDSCs and increasing IFN-Υ-secreting T-cells in the tumor microenvironment, with similar outcomes to anti-PDL1 mAb. Conclusions: Blocking DC-HIL function is a potentially useful treatment for at least colorectal cancer with high blood levels of DC-HIL+ MDSCs.