Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression in Melanoma
| Autor: | Ting Sun, Xiao Dan Peng, Zhi Ling Li, Rui Yan Wu, Rong Deng, Gong Kan Feng, Xiao Feng Zhu, Liang Ping Xia, Yu Hong Chen, Xue Lian Xu, Yun Yun Tang, Li Huan Zhou, Peng Fei Kong, Xuan Li, Yun Huang, Dong Yang, Ravichandran Senthilkumar, Hai Liang Zhang, Jia Mai, Yan Yu |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research Skin Neoplasms Pyridines medicine.medical_treatment B7-H1 Antigen Mice chemistry.chemical_compound 0302 clinical medicine Cell Movement Melanoma Immunity Cellular Mice Inbred BALB C biology Kinase Gene Expression Regulation Neoplastic Survival Rate Oncology 030220 oncology & carcinogenesis Female Immunotherapy Proto-oncogene tyrosine-protein kinase Src Mice Nude 03 medical and health sciences In vivo Cell Line Tumor Regorafenib PD-L1 medicine Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Neoplasm Invasiveness Protein Kinase Inhibitors Cell Proliferation business.industry Phenylurea Compounds Proto-Oncogene Proteins c-ret medicine.disease Xenograft Model Antitumor Assays Immune checkpoint Mice Inbred C57BL 030104 developmental biology chemistry Cancer research biology.protein business |
| Zdroj: | Clinical Cancer Research. 25:4530-4541 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-18-2840 |
| Popis: | 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 IFNγ-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 IFNγ or ICB. By targeting the RET–Src axis, regorafenib potently inhibited JAK1/2–STAT1 and MAPK signaling and subsequently attenuated the IFNγ-induced PD-L1 and IDO1 expression without affecting MHC-I expression much. Moreover, RET and Src co-high 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 IFNγ-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. |
| Databáze: | OpenAIRE |
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