CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic Hedgehog-Medulloblastoma model.
CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic Hedgehog-Medulloblastoma model.
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CSF 1 R抑制在小鼠Sonic Hedgehog-髓母细胞瘤模型中耗尽肿瘤相关巨噬细胞并减弱肿瘤进展
DOI：
10.1038/s41388-020-01536-0
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发表时间：
2021-01
期刊：
影响因子：
8
通讯作者：
Joyner AL
中科院分区：
文献类型：
--
作者：
Tan IL;Arifa RDN;Rallapalli H;Kana V;Lao Z;Sanghrajka RM;Sumru Bayin N;Tanne A;Wojcinski A;Korshunov A;Bhardwaj N;Merad M;Turnbull DH;Lafaille JJ;Joyner AL
肿瘤的免疫微环境可以在促进或抑制肿瘤进展中发挥关键作用，这取决于上下文。我们目前的证据表明，肿瘤相关的巨噬细胞/小胶质细胞（TAMs）可以促进髓母细胞瘤（SHH-MB）的音刺猬亚组的肿瘤进展。通过结合纵向锰增强磁共振成像（MEMRI）和散发性SHH-MB小鼠模型的免疫分析，我们发现TAMs的密度在发展为致死性疾病的约50%的肿瘤中较高。此外，减少调节性T细胞或消除Rag 1突变体中的B和T细胞不会改变SHH-MB肿瘤进展。由于TAM是肿瘤中的主要免疫成分，通常依赖于集落刺激因子1受体（CSF 1 R），因此我们用CSF 1 R抑制剂PLX 5622治疗小鼠。值得注意的是，PLX 5622在治疗四周内减少了TAM的子集，提高了小鼠存活率，并减少了大多数肿瘤的体积。此外，随着TAM的减少，浸润性细胞毒性T细胞的百分比增加，表明肿瘤环境的变化。我们在免疫活性临床前小鼠模型中的研究表明TAM在促进SHH-MB进展中具有功能性作用。因此，CSF 1 R抑制可能对SHH-MB患者亚组具有治疗潜力。
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 four 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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影响因子：
7.3
作者：
Greter M;Lelios I;Croxford AL
通讯作者：
Croxford AL
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
2.4
作者：
McNeill, Katharine A.
通讯作者：
McNeill, Katharine A.
DOI：
10.1158/1078-0432.ccr-14-1144
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Margol AS;Robison NJ;Gnanachandran J;Hung LT;Kennedy RJ;Vali M;Dhall G;Finlay JL;Erdreich-Epstein A;Krieger MD;Drissi R;Fouladi M;Gilles FH;Judkins AR;Sposto R;Asgharzadeh S
通讯作者：
Asgharzadeh S
影响因子：
16.2
作者：
Machold, R;Fishell, G
通讯作者：
Fishell, G