Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma

Victor Maximov,Tobey J Macdonald,Vasilisa A Rudneva,Kelly C Goldsmith,Zhihong Chen,Dolores Hambardzumyan,Paul A Northcott,Yun Wei,M Hope Robinson,Anna M Kenney,Nithya S Shanmugam,Cameron J Herting

doi:10.1038/s41467-019-10458-9

Abstract

Medulloblastoma, which is the most common malignant paediatric brain tumour, has a 70% survival rate, but standard treatments often lead to devastating life-long side effects and recurrence is fatal. One of the emerging strategies in the search for treatments is to determine the roles of tumour microenvironment cells in the growth and maintenance of tumours. The most attractive target is tumour-associated macrophages (TAMs), which are abundantly present in the Sonic Hedgehog (SHH) subgroup of medulloblastoma. Here, we report an unexpected beneficial role of TAMs in SHH medulloblastoma. In human patients, decreased macrophage number is correlated with significantly poorer outcome. We confirm macrophage anti-tumoural behaviour in both ex vivo and in vivo murine models of SHH medulloblastoma. Taken together, our findings suggest that macrophages play a positive role by impairing tumour growth in medulloblastoma, in contrast to the pro-tumoural role played by TAMs in glioblastoma, another common brain tumour.

Highlights

Medulloblastoma, which is the most common malignant paediatric brain tumour, has a 70% survival rate, but standard treatments often lead to devastating life-long side effects and recurrence is fatal
We developed an ex vivo assay to assess the effects of microglia or bone marrow-derived macrophages (BMDMs) effect on organotypic tumour slices, which allows us to closely model in vivo effects
We found that there was a significant increase in AIF1 transcription in Sonic Hedgehog (SHH) medulloblastoma, moreso than in any other medulloblastoma subgroup (P < 0.0001, one-way ANOVA; Fig. 1a)

Summary

Introduction

Medulloblastoma, which is the most common malignant paediatric brain tumour, has a 70% survival rate, but standard treatments often lead to devastating life-long side effects and recurrence is fatal. It was reported that of all the medulloblastoma subgroups, human SHH has the greatest number of TAMs, as well as increased expression of some macrophage-associated genes[10,11,12]. We demonstrate that deletion of the C−C chemokine receptor type-2 gene (Ccr2) from the host of allografted tumours, or using a pharmacological approach by treating tumour-bearing mice with two CSF1R inhibitors, significantly decreases survival time of tumour-bearing mice compared to vehicle treatment. Overall, these findings demonstrate that TAMs have an important role in inhibiting tumour growth in medulloblastoma. Further investigation of immune system interactions with tumour cells in medulloblastoma is warranted, as it could provide an intriguing route to the development of novel treatment approaches by leveraging the host immune system

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Results

Conclusion