Genetic and Pharmacological Targeting of CSF-1/CSF-1R Inhibits Tumor-Associated Macrophages and Impairs BRAF-Induced Thyroid Cancer Progression

Advanced human thyroid cancers are densely infiltrated with tumor-associated macrophages (TAMs) and this correlates with a poor prognosis. We used BRAF-induced papillary thyroid cancer (PTC) mouse models to examine the role of TAMs in PTC progression. Following conditional activation of BRAFV600E in murine thyroids there is an increased expression of the TAM chemoattractants Csf-1 and Ccl-2. This is followed by the development of PTCs that are densely infiltrated with TAMs that express Csf-1r and Ccr2. Targeting CCR2-expressing cells during BRAF-induction reduced TAM density and impaired PTC development. This strategy also induced smaller tumors, decreased proliferation and restored a thyroid follicular architecture in established PTCs. In PTCs from mice that lacked CSF-1 or that received a c-FMS/CSF-1R kinase inhibitor, TAM recruitment and PTC progression was impaired, recapitulating the effects of targeting CCR2-expressing cells. Our data demonstrate that TAMs are pro-tumorigenic in advanced PTCs and that they can be targeted pharmacologically, which may be potentially useful for patients with advanced thyroid cancers.晚期人类甲状腺癌被肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）密集浸润，且该现象与不良预后密切相关。本研究采用BRAF诱导型乳头状甲状腺癌（papillary thyroid cancer, PTC）小鼠模型，探究TAMs在PTC进展中的作用。在小鼠甲状腺内条件性激活BRAFV600E后，TAM趋化因子Csf-1与Ccl-2的表达水平显著升高。随后，甲状腺内会形成被表达Csf-1r与Ccr2的TAMs密集浸润的PTC病灶。在BRAF诱导过程中靶向表达CCR2的细胞，可降低TAM浸润密度并抑制PTC的发生发展。该干预策略还可使已形成的PTC肿瘤体积缩小、增殖活性降低，并恢复甲状腺滤泡结构。在缺失CSF-1或接受c-FMS/CSF-1R激酶抑制剂治疗的小鼠的PTC组织中，TAM招募与PTC进展均受到显著抑制，这与靶向表达CCR2的细胞所产生的生物学效应一致。本研究数据表明，TAMs在晚期PTC中具有促肿瘤发生的作用，且可通过药理学手段进行靶向干预，该策略或可为晚期甲状腺癌患者提供潜在的临床治疗选择。