TY - JOUR
T1 - Activation of the receptor tyrosine kinase AXL regulates the immune microenvironment in glioblastoma
AU - Sadahiro, Hirokazu
AU - Kang, Kyung Don
AU - Gibson, Justin T.
AU - Minata, Mutsuko
AU - Yu, Hai
AU - Shi, Junfeng
AU - Chhipa, Rishi
AU - Chen, Zhihong
AU - Lu, Songjian
AU - Simoni, Yannick
AU - Furuta, Takuya
AU - Sabit, Hemragul
AU - Zhang, Suojun
AU - Bastola, Soniya
AU - Yamaguchi, Shinobu
AU - Alsheikh, Hebaallah
AU - Komarova, Svetlana
AU - Wang, Jun
AU - Kim, Sung Hak
AU - Hambardzumyan, Dolores
AU - Lu, Xinghua
AU - Newell, Evan W.
AU - DasGupta, Biplab
AU - Nakada, Mitsutoshi
AU - Lee, L. James
AU - Nabors, Burt
AU - Norian, Lyse A.
AU - Nakano, Ichiro
N1 - Publisher Copyright:
2018 American Association for Cancer Research.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85048049547&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-2433
DO - 10.1158/0008-5472.CAN-17-2433
M3 - Article
C2 - 29531161
AN - SCOPUS:85048049547
SN - 0008-5472
VL - 78
SP - 3002
EP - 3013
JO - Cancer Research
JF - Cancer Research
IS - 11
ER -