Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 14, Pages 4530-4541Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-2840
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Funding
- National Key R&D Program of China [2017YFC0908501]
- Natural Science Foundation of China [81630079, 81772624, 81572605, 81572732, 81803006, 81802789]
- Science and Technology Project of Guangzhou [201803010007]
- Natural Science Foundation of Guangdong Province [2017A030313481]
- Fundamental Research Funds for the Central Universities of China [17ykjc25]
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Purpose: Immune checkpoint blockade (ICB) therapy induces durable tumor regressions in a minority of patients with cancer. In this study, we aimed to identify kinase inhibitors that were capable of increasing the antimelanoma immunity. Experimental Design: Flow cytometry-based screening was performed to identify kinase inhibitors that can block the IFN gamma-induced PD-L1 expression in melanoma cells. The pharmacologic activities of regorafenib alone or in combination with immunotherapy in vitro and in vivo were determined. The mechanisms of regorafenib were explored and analyzed in melanoma patients treated with or without anti-PD-1 using The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. Results: Through screening of a kinase inhibitor library, we found approximately 20 agents that caused more than half reduction of cell surface PD-L1 level, and regorafenib was one of the most potent agents. Furthermore, our results showed that regorafenib, in vitro and in vivo, strongly promoted the antitumor efficacy when combined with IFN gamma or ICB. By targeting the RET-Src axis, regorafenib potently inhibited JAK1/2-STAT1 and MAPK signaling and subsequently attenuated the IFN gamma-induced PD-L1 and IDO1 expression without affecting MHC-I expression much. Moreover, RET and Src cohigh expression was an independent unfavorable prognosis factor in melanoma patients with or without ICB through inhibiting the antitumor immune response. Conclusions: Our data unveiled a new mechanism of alleviating IFN gamma-induced PD-L1 and IDO1 expression and provided a rationale to explore a novel combination of ICB with regorafenib clinically, especially in melanoma with RET/Src axis activation.
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