DC-HIL/GpNMB is a negative regulator of tumor response to immune checkpoint inhibitors

Jin Sung Chung, Vijay Ramani, Masato Kobayashi, Farjana Fattah, Vinita Popat, Song Zhang, Ponciano D. Cruz, David E. Gerber, Kiyoshi Ariizumi

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Experimental Design: Plasma samples were collected from patients with advanced non-small cell lung carcinoma (NSCLC) (n ¼ 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-DC-HIL gene, injection of DC-HIL-expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression. Results: Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients (n ¼ 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-HILþMDSC or induction of sDC-HIL expression. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1449-1459
Number of pages11
JournalClinical Cancer Research
Volume26
Issue number6
DOIs
StatePublished - Mar 15 2020

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chung, J. S., Ramani, V., Kobayashi, M., Fattah, F., Popat, V., Zhang, S., Cruz, P. D., Gerber, D. E., & Ariizumi, K. (2020). DC-HIL/GpNMB is a negative regulator of tumor response to immune checkpoint inhibitors. Clinical Cancer Research, 26(6), 1449-1459. https://doi.org/10.1158/1078-0432.CCR-19-2360