CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic hedgehog-medulloblastoma model Journal Article

   

Authors:	Tan, I. L.; Arifa, R. D. N.; Rallapalli, H.; Kana, V.; Lao, Z.; Sanghrajka, R. M.; Bayin, N. S.; Tanne, A.; Wojcinski, A.; Korshunov, A.; Bhardwaj, N.; Merad, M.; Turnbull, D. H.; Lafaille, J. J.; Joyner, A. L.
Article Title:	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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords:	adult; controlled study; unclassified drug; cancer growth; nonhuman; nuclear magnetic resonance imaging; cd8+ t lymphocyte; mouse; enzyme inhibition; tumor volume; animal experiment; animal model; b lymphocyte; regulatory t lymphocyte; infant; contrast enhancement; medulloblastoma; cd4+ t lymphocyte; cytotoxic t lymphocyte; lymphocytic infiltration; protein inhibitor; colony stimulating factor 1; tumor microenvironment; tumor-associated macrophage; colony stimulating factor 1 receptor; human; priority journal; article; plx 5622; manganese enhanced magnetic resonance imaging
Journal Title:	Oncogene
Volume:	40
Issue:	2
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Date Published:	2021-01-14
Start Page:	396
End Page:	407
Language:	English
DOI:	10.1038/s41388-020-01536-0
PUBMED:	33159168
PROVIDER:	scopus
PMCID:	PMC7855734
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85095457870&doi=10.1038%2fs41388-020-01536-0&partnerID=40&md5=d26ab32ca7fd411b7e983db7797b3ce4
Notes:	Article -- Export Date: 1 February 2021 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/176226