Abstract Background Tumor-associated macrophages (TAMs) are key contributors to the brain tumor microenvironment. However, their role in medulloblastoma (MB) progression and chemoresistance remains elusive. Methods We utilized CD11b-diphtheria toxin receptor (DTR)/Ptch1-deficient MB model to genetically delete TAMs. NeuroD2-SmoA1 MB mice were treated with CSF1R inhibitor PLX3397, PI3K inhibitor buparlisib, and a combination of PLX3397 with chemotherapy to examine the functional significance of TAMs in MB. Tumor tissues and cell co-culture system were analyzed using RNA sequencing (RNA-seq), Western blotting, flow cytometry, immunohistochemistry, quantitative PCR and 3D bioprinted MB mono-culture to delineate mechanistic interactions. Results Myeloid-derived TAMs are abundant in MB tissues and primarily exhibit M2-like polarization. We demonstrate that TAMs depletion, achieved either genetically via diphtheria toxin (DT) or pharmacologically via PLX3397-mediated preferential targeting of M2-like TAMs, markedly downregulates Zic1 expression and impedes MB growth. Mechanistically, M2-like TAMs secreted high levels of IGF1 to activate the PI3K/mTOR/Zic1 axis in MB cells; whereas the PI3K inhibitor buparlisib effectively reduced the population of Zic1-expresssing cells and restricted MB growth. Notably, the PI3K/mTOR/Zic1 axis was demonstrated to confer chemoresistance. While chemotherapy exacerbates M2-like TAMs accumulation within MB, combining PLX3397 with chemotherapy abrogates this infiltration and attenuates IGF1/PI3K/Zic1 signaling axis. This combination strategy synergistically inhibits tumor growth and extends survival in mice. Conclusion Our findings demonstrate that inhibiting the TAMs-induced IGF1/PI3K/Zic1 signaling axis results in MB regression and chemosensitization. These results underscore the therapeutic potential of combining clinical CSF1R inhibitor with standard chemotherapy as an effective treatment strategy for SHH MB.
Pang et al. (Thu,) studied this question.