DC-HIL/Gpnmb Is a Negative Regulator of Tumor Response to Immune Checkpoint Inhibitors

• Published in: Clinical cancer research 2020-03, Vol.26 (6), p.1449-1459
• Main Authors: Chung, Jin-Sung, Ramani, Vijay, Kobayashi, Masato, Fattah, Farjana, Popat, Vinita, Zhang, Song, Cruz, Jr, Ponciano D, Gerber, David E, Ariizumi, Kiyoshi
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal - pharmacology; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Immunologic Factors - metabolism; Immunotherapy - methods; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Male; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Membrane Glycoproteins - immunology; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Middle Aged; Myeloid-Derived Suppressor Cells - immunology; Skin Neoplasms - immunology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Skin Neoplasms - therapy
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-2360

Immune checkpoint inhibitors (ICI) benefit only a minority of treated patients with cancer. Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitory mechanisms, we examined whether DC-HIL expression regulates ICI responsiveness. Plasma samples were collected from patients with advanced non-small cell lung carcinoma (NSCLC) ( = 76) at baseline and/or follow-up after ICI monotherapy. Blood-soluble DC-HIL (sDC-HIL) was determined and analyzed for correlation with the early tumor response. To study the mechanisms, we measured effect of anti-DC-HIL versus anti-PDL1 mAb on growth of mouse tumor cells in experimentally metastatic lung. Influence of DC-HIL to anti-PDL1 treatment was assessed by changes in tumor response after deletion of host- gene, injection of DC-HIL-expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression. Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients ( = 28) for fluctuation with time, nonresponders (14/15 cases) showed increasing or persistently elevated levels. Responders (12/13) had decreasing or persistently low levels. Among various tumors, B16 melanoma exhibited resistance to anti-PDL1 but responded to anti-DC-HIL mAb. Using B16 melanoma and LL2 lung cancer, we showed that deletion of host-derived DC-HIL expression converted the resistant tumor to one responsive to anti-PDL1 mAb. The responsive state was reversed by infusion of DC-HIL MDSC or induction of sDC-HIL expression. sDC-HIL in the blood and probably DC-HIL receptor expressed by MDSC play an important role in regulating response to ICI in advanced NSCLC.