Inhibition of BACE1 Facilitates Macrophage-based Immunotherapy to Suppress Malignant Growth of Glioblastoma [post]

Kui Zhai, Zhi Huang, Weiwei Tao, Xiaoguang Fang, Qian Huang, Xiaoxia Li, George Stark, Thomas Hamilton, Shideng Bao
2020 unpublished
Malignant tumors, including glioblastoma (GBM), contain abundant tumor-associated macrophages (TAMs) that mainly promote tumor growth and therapeutic resistance. Reprograming tumor-promoting TAMs (pTAMs) into tumor-suppressive TAMs (sTAMs) represents an attractive therapeutic strategy. We discovered that inhibition of the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) by MK-8931 potently redirects pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells to suppress the
more » ... ls to suppress the malignant growth of GBM. Moreover, low doses of radiation markedly enhance TAM infiltration and synergize with MK-8931 treatment. BACE1 is preferentially expressed by pTAMs in human GBMs and is required for maintaining pTAM polarization through trans-IL-6/sIL-6R/STAT3 signaling. As several BACE1 inhibitors, including MK-8931, previously developed for Alzheimer's disease, were shown in clinical trials to be safe for humans, repurposing these inhibitors for cancer therapy should be straightforward. Collectively, this study offers a promising therapeutic approach, through inhibition of BACE1, to facilitate the macrophage-based tumor immunotherapy.
doi:10.21203/ fatcat:r4h3dtw2qjen3kqwdjrpl7gbte