Blocking Monocytic Myeloid-Derived Suppressor Cell Function via Anti-DC-HIL/GPNMB Antibody Restores the In Vitro Integrity of T Cells from Cancer Patients

• Published in: Clinical cancer research 2019-01, Vol.25 (2), p.828-838
• Main Authors: Kobayashi, Masato, Chung, Jin-Sung, Beg, Muhammad, Arriaga, Yull, Verma, Udit, Courtney, Kevin, Mansour, John, Haley, Barbara, Khan, Saad, Horiuchi, Yutaka, Ramani, Vijay, Harker, David, Gopal, Purva, Araghizadeh, Farshid, Cruz, Jr, Ponciano D, Ariizumi, Kiyoshi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Immunological - pharmacology; Cell Line, Tumor; Disease Progression; Humans; Immunophenotyping; Interferon-gamma; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Membrane Glycoproteins - antagonists & inhibitors; Mice; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-0330

Blocking the function of myeloid-derived suppressor cells (MDSC) 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 mAb as an MDSC-targeting cancer treatment. Patients with metastatic cancer ( = 198) were analyzed by flow cytometry for DC-HIL or PDL1 expression on blood CD14 HLA-DR MDSCs. Their suppressor function was assessed by coculture 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 antitumor activity of the mAb was evaluated by attenuated growth of colon cancers in mice. Patients with metastatic cancer had high blood levels of DC-HIL MDSCs compared with healthy controls. Anti-DC-HIL mAb reversed the 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 IFNγ in cocultures. DC-HIL is not expressed by colorectal cancer cells but by CD14 cells infiltrating the tumor. Finally, anti-DC-HIL mAb attenuated growth of preestablished colon tumors by reducing MDSCs and increasing IFNγ-secreting T cells in the tumor microenvironment, with similar outcomes to anti-PDL1 mAb. Blocking DC-HIL function is a potentially useful treatment for at least colorectal cancer with high blood levels of DC-HIL MDSCs. .