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

I. Li Tan, Raquel Duque Nascimento Arifa, Harikrishna Rallapalli, Veronika Kana, Zhimin Lao, Reeti Mayur Sanghrajka, N. Sumru Bayin, Antoine Tanne, Alexandre Wojcinski, Andrey Korshunov, Nina Bhardwaj, Miriam Merad, Daniel H. Turnbull, Juan J. Lafaille, Alexandra L. Joyner

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish
Pages (from-to)396-407
Number of pages12
JournalOncogene
Volume40
Issue number2
DOIs
StatePublished - 14 Jan 2021

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