Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma

• Type of Material: Article
• Authors: Hirokazu Sadahiro, University of Alabama Birmingham; Kyung-Don Kang, University of Alabama Birmingham; Justin T. Gibson, University of Alabama Birmingham; Mutsuko Minata, University of Alabama Birmingham; Hai Yu, University of Alabama Birmingham; Junfeng Shi, Ohio State University; Rishi Chhipa, Cincinnati Children’s Hospital Medical Center; Zhihong Chen, Emory University; Songjian Lu, University of Pittsburgh; Yannick Simoni, Agency for Science Technology and Research; Takuya Furuta, Kurume University; Hemragul Sabit, Kanazawa University; Suojun Zhang, University of Alabama Birmingham; Soniya Bastola, University of Alabama Birmingham; Shinobu Yamaguchi, University of Alabama Birmingham; Hebaallah Alsheikh, University of Alabama Birmingham; Svetlana Komarova, University of Alabama Birmingham; Jun Wang, University of Alabama Birmingham; Sung-Hak Kim, Chonnam National University; Dolares Hambardzumyan, Emory University
• Language: English
• Date: 2018-06-01
• Publisher: American Association for Cancer
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2018 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-17-2433
• Title of Journal or Parent Work: Cancer Research
• Volume: 78
• Issue: 11
• Start Page: 3002
• End Page: 3013
• Grant/Funding Information: This study was supported by following NIH grants: P01CA163205 (I. Nakano); R01NS083767 (I. Nakano); R21CA175875 (I. Nakano); R01NS087913 (I. Nakano); R01CA183991 (I. Nakano).
• Keywords: DEPENDENT MANNER; RADIATION; PROSTATE-CANCER; GLIOMA STEM-CELLS; Science & Technology; Life Sciences & Biomedicine; THERAPEUTIC TARGET; BLOCKADE; GROWTH-ARREST; Oncology; CHECKPOINT; TUMORIGENICITY; HETEROGENEITY
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NFkB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for patients with GBM. Our results suggest that the PROS1–AXL pathway regulates intrinsic mesenchymal signaling and the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors. Significance: These findings suggest that development of combination treatments of AXL and immune checkpoint inhibitors may provide benefit to patients with GBM.