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

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 NFκB 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. These findings suggest that development of combination treatments of AXL and immune checkpoint inhibitors may provide benefit to patients with GBM. .

A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial–Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer

“…The role of mTORC2 was further supported by the BV2 microglia in vitro model where the BV2-CM can directly promote P-EGFR and P-AKT via a tumor cell mTORC2-dependent manner. Although these observations are consistent with the recent reports that microglia cells could enhance outgrowth of brain metastatic breast tumor cells (31) and glioblastoma cells (39), future studies are required to elucidate the mechanistic details on mTORC2 mechanism of action.…”

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…Inhibition of CSF1R attenuates the recruitment of TAMs and also increases the CD8 + T cell infiltration (Strachan et al, 2013) (Figure 1). Another regulator of the immune microenvironment is the receptor tyrosine kinase AXL that is expressed in TAMs (Sadahiro et al, 2018). Its inhibition in a GB mouse model was (1) Monocytes are recruited to the tumor where they differentiate into macrophages.…”

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

“…On the other hand, BLZ945 modulated the inflammatory activation of GAMs, favoring their antitumor activities which explains the beneficial effects observed with the treatment (see next section). In a different preclinical model of glioblastoma, consisting of tumors derived by implantation of GSCs lacking tumor suppressor phosphatase and tensin homolog, p53 and neurofibromin 1 (NF1), BLZ945 efficiently blocked GAMs' recruitment at tumor site together with reducing tumor growth [37] . Interestingly, a first-in-human study employing BLZ945 (NCT02829723) is currently ongoing.…”

“…relevant antiproliferative effects on different preclinical models of glioblastoma. The drug, namely BGB324 (also known as R428) significantly increased neurological free survival particularly in the group of mice bearing high-AXL expressing tumors [37] . In addition, BGB324 treatment reduced the amount of infiltrating CD45 + leukocytes and CD11b + GAMs.…”

“…In addition, BGB324 treatment reduced the amount of infiltrating CD45 + leukocytes and CD11b + GAMs. Interestingly, the anti PD-1 inhibitor nivolumab increased the protective effects of BG324, and effectively prolonged the survival of tumor bearing mice [37] . Nivolumab per se displayed no survival benefits in these animals, while increasing both AXL kinase activity and GAMs' tumor infiltration.…”