Wednesday, February 5, 2025
2/5/2025
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.
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