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Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma Hirokazu Sadahiro1,2, Kyung-Don Kang1, Justin T

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Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma Hirokazu Sadahiro1,2, Kyung-Don Kang1, Justin T Published OnlineFirst March 12, 2018; DOI: 10.1158/0008-5472.CAN-17-2433 Cancer Tumor Biology and Immunology Research Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma Hirokazu Sadahiro1,2, Kyung-Don Kang1, Justin T. Gibson3, Mutsuko Minata1, Hai Yu1,4, Junfeng Shi5, Rishi Chhipa6, Zhihong Chen7, Songjian Lu8, Yannick Simoni9, Takuya Furuta10, Hemragul Sabit11, Suojun Zhang1,12, Soniya Bastola1, Shinobu Yamaguchi1, Hebaallah Alsheikh1, Svetlana Komarova1, Jun Wang1, Sung-Hak Kim13, Dolores Hambardzumyan7, Xinghua Lu8,EvanW.Newell9, Biplab DasGupta6, Mitsutoshi Nakada11, L. James Lee5, Burt Nabors1, Lyse A. Norian3,14, and Ichiro Nakano1,14 Abstract Glioblastoma (GBM) is a lethal disease with no effective ther- We also found that treatment of GSC-derived mouse GBM tumors apies available. We previously observed upregulation of the TAM with nivolumab, a blocking antibody against the immune check- (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL point protein PD-1, increased intratumoral macrophages/micro- in mesenchymal GBM and showed that knockdown of AXL glia and activation of AXL. Combinatorial therapy with nivolumab induced apoptosis of mesenchymal, but not proneural, glioma plus BGB324 effectively prolonged the survival of mice bearing sphere cultures (GSC). In this study, we report that BGB324, a GBM tumors. Clinically, expression of AXL or PROS1 was associ- novel small molecule inhibitor of AXL, prolongs the survival of ated with poor prognosis for patients with GBM. Our results immunocompromised mice bearing GSC-derived mesenchymal suggest that the PROS1–AXL pathway regulates intrinsic mesen- GBM-like tumors. We show that protein S (PROS1), a known chymal signaling and the extrinsic immune microenvironment, ligand of other TAM receptors, was secreted by tumor-associated contributing to the growth of aggressive GBM tumors. macrophages/microglia and subsequently physically associated Significance: These findings suggest that development of with and activated AXL in mesenchymal GSC. PROS1-driven combination treatments of AXL and immune checkpoint inhibi- phosphorylation of AXL (pAXL) induced NFkBactivationin tors may provide benefit to patients with GBM. Cancer Res; 78(11); mesenchymal GSC, which was inhibited by BGB324 treatment. 3002–13. Ó2018 AACR. 1Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama. 2Department of Neurosurgery, Yamaguchi University, Introduction 3 Yamaguchi, Japan. Department of Nutrition Sciences, University of Alabama at Glioblastoma (GBM) is among the most lethal of adult cancers. 4 Birmingham, Birmingham, Alabama. Department of Neurosurgery, The First The median survival of patients remains less than 2 years despite Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. 5Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, the current available therapies, including surgery, radiation, and Ohio. 6Division of Oncology, Cincinnati Children's Hospital Medical Center, chemotherapy; development of more effective therapies is urgent- Cincinnati, Ohio. 7Department of Pediatrics, Aflac Cancer and Blood Disorders ly needed. Center, Children's Healthcare of Atlanta, Emory University School of Medicine, We have recently reported that increased expression of the 8 Atlanta, Georgia. Department of Biomedical Informatics, University of receptor tyrosine kinase AXL is significantly correlated with poor 9 Pittsburgh, Pittsburgh, Pennsylvania. Singapore Immunology Network, Agency prognosis in GBM. Furthermore, we found that AXL expression is for Science Technology and Research, Singapore, and the Nanyang Techno- logical University School of Biological Sciences, Singapore. 10Department of elevated in the mesenchymal (MES) GBM subtype (1). AXL, along Pathology, Kurume University School of Medicine, Kurume, Japan. 11Department with TYRO3 and MERTK, belong to the TAM family of kinases, of Neurosurgery, Division of Neuroscience, Graduate School of Medical Science, which are activated by the growth arrest-specific protein 6 (GAS6) Kanazawa University, Kanazawa, Japan. 12Department of Neurosurgery, Tongji and protein S (PROS1) ligands. Previous reports have shown that Hospital, Tongji Medical College, Huazhong University of Science and Technol- GAS6 binds all three receptors, whereas PROS1 interacts with 13 ogy, Wuhan, China. Department of Animal Science, College of Agriculture TYRO3 and MERTK, but not with AXL (2–4). GAS6-driven AXL and Life Sciences, Chonnam National University, Gwangju, Republic of Korea. 14UAB Comprehensive Cancer Center, University of Alabama at Birmingham, signaling is known to have various tumor-promoting effects. For Birmingham, Alabama. example, acute myeloid leukemia (AML) cells induce bone mar- row–derived stromal cells to express and secrete GAS6, which in Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). turn mediates proliferation, survival, and chemoresistance of AXL-expressing AML cells (5). In lung cancers that express a H. Sadahiro and K.-D. Kang contributed equally to this article. mutant form of the EGFR associated with acquired resistance to Corresponding Author: Ichiro Nakano, University of Alabama at Birmingham, tyrosine kinase inhibitors, expression of both AXL and GAS6 is 410F WTI UAB Comprehensive Cancer Center, Birmingham, AL 35243. Phone: increased (6). Elucidation of these pro-oncogenic roles of AXL has 614-292-0358; Fax: 614-292-0358; E-mail: [email protected] resulted in increasing interest in AXL as a clinical target. In 2013, a doi: 10.1158/0008-5472.CAN-17-2433 clinical trial for a small molecule AXL inhibitor, BGB324 (also Ó2018 American Association for Cancer Research. known as R428), was launched for the treatment of colon cancer 3002 Cancer Res; 78(11) June 1, 2018 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst March 12, 2018; DOI: 10.1158/0008-5472.CAN-17-2433 Targeting AXL in Glioblastoma (7). More recently, a second clinical trial investigating BGB324 in tandem repeat (STR) analysis. GBM sphere cultures (1, 17–19) the AML and non–small cell lung cancer settings has been initi- were maintained in DMEM/F12/Glutamax (Gibco) with EGF ated in the United States (NCT02424617). (Peprotech), basic fibrous growth factor (bFGF; PeproTech), In addition to direct effects on tumor cells, in some cancers, AXL heparin (Sigma), and B27 (neuroBrew-21 w/o vitamin A, MACS). also appears to promote immune suppression through transcrip- EGF, bFGF, and heparin were added twice weekly. The cell lines tional regulation of the immune checkpoint ligand, PD-L1 (8). were cultivated for no longer than 30 passages. Mouse GBM nivolumab and pembrolizumab were the first two checkpoint sphere cultures were established as described previously (20) and inhibitors designed to target the PD-L1 receptor, PD-1. In 2014, cultured in the same medium described above. The cell lines were both were approved by the FDA for the treatment of unresectable tested negative for mycoplasma contamination. and metastatic melanoma (9). In a clinical trial for patients with metastatic melanoma, treatment with nivolumab alone, or in In vitro AXL and PDGFRa mRNA detection by nanochannel combination with the cytotoxic T-lymphocyte-associated antigen- electroporation -delivered molecular beacon probes 4 (CTLA-4) antibody, ipilimumab, resulted in significantly longer AXL molecular beacon (MB; Cy5-labeled) and PDGFRa MB patient survival than did treatment with ipilimumab alone (10). (FAM-labeled) were codelivered into GSCs (GBM157) by 3D In the setting of GBM, several preclinical studies investigating nanochannel electroporation (NEP) chips designed for large-scale immune checkpoint inhibitors have demonstrated that antibo- uniform and benRign cell transfection (21, 22). The cells were dies targeting CTLA-4, PD-1, or PD-L1 produce tumor regression seeded as monolayer in 3D silicon NEP chip overnight in 10% and survival benefit in syngeneic GBM murine models (11, 12). FBS, heparin-free glioma cell culture medium before the NEP- Furthermore, combination treatment using an anti-PD-1 mAb based transfection to ensure a tight contact between cells and and localized radiation therapy increased the survival of mice nanochannel array. Before the nano-electroporation for intracel- bearing orthotopic brain tumors (13). Based on these encourag- lular delivery of MBs, the MB solution was prepared in the optimal ing preclinical data, a phase III clinical trial (NCT02017717) was concentration from 200 to 500 nmol/L and then pipetted in the initiated in 2014 to compare the efficacy of nivolumab with that reservoir on the bottom gold-coated electrode slide with 500 mLto of bevacizumab for the treatment of recurrent GBM. However, this 1 mL volume. The MBs were then NEP-injected into the single first trial failed to demonstrate nivolumab efficacy, for reasons glioma clones on the 3D NEP chip surface by applying an electric that remain unclear. Several additional clinical trials investigating field pulse with conditions of 150 to 200 V, 20 to 30 milliseconds PD-1/PD-L1 checkpoint inhibitors for the treatment of GBM, duration, across the nanochannel arrays. After 1-hour incubator, both as monotherapy, and in combination with other therapies MB hybridization with the specific target mRNA biomarker such as radiotherapy (NCT02667587), surgery (NCT02337686), gradually
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