Macrophage-based Therapy and Immune Checkpoint Blockade for Glioblastoma

Project Summary
Glioblastoma (GBM), the most lethal primary brain tumor with poor prognosis, is highly resistant to current
treatments, including immune checkpoint blockade (ICB) partially due to the immune suppressive
microenvironment. GBM harbors abundant tumor-associated macrophages (TAMs) that are critical immune
cells in the tumor microenvironment (TME). Because the majority of TAMs are tumor-promoting macrophages
(pTAMs, M2-like) that augment malignant growth, promote therapeutic resistance, and mediate immune
suppression, reprograming pTAMs into tumor-suppressive macrophages (sTAMs, M1-like) represents a
promising therapeutic strategy. As pTAMs establish the immunosuppressive microenvironment that negatively
impacts current immunotherapy, redirecting pTAMs into sTAMs not only activates macrophage phagocytosis of
glioma cells but may also remodel the immune microenvironment to facilitate current ICB. To identify small
molecules that can reprogram pTAMs into sTAMs to promote macrophage phagocytosis of glioma cells, we
designed a cell-based fluorescent screening assay, using GFP-labeled iPSC-derived macrophages and
tdTomato-expressing glioma cells including glioma stem cells (GSCs) to discover drug candidates and
corresponding molecular targets. To this end, we found that several specific inhibitors of BACE1 (β-site
amyloid precursor protein cleaving enzyme 1) could effectively stimulate macrophage phagocytosis to engulf
glioma cells including GSCs, and thus identified BACE1 as a therapeutic target to reprogram pTAMs into
sTAMs. We demonstrated that BACE1 is preferentially expressed by pTAMs in human GBMs and is required
for maintaining pTAM polarization. Importantly, pharmacological inhibition of BACE1 by its inhibitor MK-8931
(Verubecestat) potently redirected pTAMs into sTAMs and promoted macrophage phagocytosis of glioma cells
to inhibit GBM growth. Furthermore, we found that low doses of radiation (IR) markedly enhanced TAM
infiltration and synergized with MK-8931 treatment to suppress GBM tumor growth. As several BACE1
inhibitors including MK-8931, initially developed for Alzheimer's disease, have been demonstrated to be safe
for humans in clinical trials, repurposing these inhibitors for the macrophage-based cancer therapy should
straightforward and promising. As abundant pTAMs largely contribute to the immune suppressive
microenvironment, reprograming pTAMs into sTAMs through BACE1 inhibition may remodel the TME to
facilitate current ICB. Thus, we hypothesize that reprograming pTAMs into sTAMs through
pharmacological inhibition of BACE1 synergizes with current immune checkpoint inhibition to improve
therapeutic efficacy for GBM. We will accomplish our objectives through the following aims: (1) We will
assess the effect of reprograming pTAMs into sTAMs on the immune microenvironment in GBM; and (2) We
evaluate the therapeutic impact of TAM-based therapy in combination with current ICB for GBM. The outcomes
will inform future clinical trials to improve treatment for GBM and potentially brain metastases.

Grant Number: 5R01CA277966-03
NIH Institute/Center: NIH
Principal Investigator: Shideng Bao