CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic Hedgehog-Medulloblastoma model

Abstract

The immune microenvironment of tumors can play a critical role in promoting or inhibiting tumor progression depending on the context. We present evidence that tumor-associated macrophages/microglia (TAMs) can promote tumor progression in the sonic hedgehog subgroup of medulloblastoma (SHH-MB). By combining longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) and immune profiling of a sporadic mouse model of SHH-MB, we found the density of TAMs is higher in the ~50% of tumors that progress to lethal disease. Furthermore, reducing regulatory T cells or eliminating B and T cells in Rag1 mutants does not alter SHH-MB tumor progression. As TAMs are a dominant immune component in tumors and are normally dependent on colony-stimulating factor 1 receptor (CSF1R), we treated mice with a CSF1R inhibitor, PLX5622. Significantly, PLX5622 reduces a subset of TAMs, prolongs mouse survival, and reduces the volume of most tumors within 4 weeks of treatment. Moreover, concomitant with a reduction in TAMs the percentage of infiltrating cytotoxic T cells is increased, indicating a change in the tumor environment. Our studies in an immunocompetent preclinical mouse model demonstrate TAMs can have a functional role in promoting SHH-MB progression. Thus, CSF1R inhibition could have therapeutic potential for a subset of SHH-MB patients.

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Fig. 1: Increased number of TAMs is associated with tumor progression in a sporadic SHH-MB mouse model.
Fig. 2: The amount of immune cell infiltration in human SHH-MB samples does not correlate with driver mutation.
Fig. 3: Depletion of Tregs or T cells in Atoh1-SmoM2 mice does not alter mouse survival.
Fig. 4: Depletion of TAMs prolongs mouse survival and blocks tumor progression in most Atoh1-SmoM2 mice.
Fig. 5: Atoh1-SmoM2 tumors treated for 4 weeks with PLX show a decrease of monocytes/macrophages and an increase of CD8 cytotoxic T cells.
Fig. 6: Depletion of TAMs in Atoh1-SmoM2 mice leads to an increase of pro-inflammatory T cells.
Fig. 7: Depletion of TAMs in Atoh1-SmoM2 mice leads to a pro-inflammatory tumor microenvironment.

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Acknowledgements

We thank the Joyner lab members for helpful discussions and comments on the manuscript. We are grateful to Andrey Rymar and Parmveer Singh at Plexxikon for providing the PLX5622 used in these studies. We appreciate the technical assistance from Daniel Stephen, and Yu-Jung Chen. We also thank the Center for comparative medicine and pathology and the Integrated Genomics Operation (IGO) core facilities of MSKCC for outstanding technical support. This work was supported by the following grants: R01CA192176 (ALJ), MSKCC Brain Tumor Center fellowship (AW), and a National Cancer Institute Cancer Center Support Grant [P30 CA008748-48].

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Tan, IL., Arifa, R.D.N., Rallapalli, H. et al. CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic Hedgehog-Medulloblastoma model. Oncogene (2020). https://doi.org/10.1038/s41388-020-01536-0

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