PDF(Pubmed)
Abstract：
Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both in vitro and in vivo. When co-cultured with monocytes, CAFs attracted monocytes and induced their differentiation into M2 macrophages. Immunohistology of surgically resected human CRC specimens and orthotopically transplanted mouse tumors revealed a correlation between numbers of CAFs and numbers of M2 macrophages. In a mouse model of CRC orthotopic transplantation, treatment with an inhibitor of the colony-stimulating factor-1 receptor (PLX3397) depleted M2 macrophages and increased CD8-positive T cells infiltrating the tumor nest. While this treatment had a minor effect on tumor growth, combining PLX3397 with anti-PD-1 antibody significantly reduced tumor growth. RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC.
摘要：
已知肿瘤相关巨噬细胞(TAMs)和癌症相关成纤维细胞(CAFs)在肿瘤的发展和进展中起支持作用。但它们在结直肠癌（CRC）中的相互作用仍不清楚。这里,我们研究了结肠癌衍生的CAFs对TAM分化的影响，迁移,和肿瘤免疫，在体外和体内。当与单核细胞共培养时，CAF吸引单核细胞并诱导其分化为M2巨噬细胞。手术切除的人CRC标本和原位移植的小鼠肿瘤的免疫组织学显示CAF的数量与M2巨噬细胞的数量之间存在相关性。在CRC原位移植的小鼠模型中，用集落刺激因子-1受体（PLX3397）的抑制剂治疗耗尽了M2巨噬细胞，并增加了CD8阳性T细胞浸润了肿瘤巢。虽然这种治疗对肿瘤生长影响较小，PLX3397与抗PD-1抗体联合显著降低肿瘤生长。联合治疗后的RNA-seq显示肿瘤免疫的激活。总之,在CRC肿瘤免疫微环境中，CAFs参与M2巨噬细胞分化的诱导和动员，癌症免疫疗法和PLX3397的组合可能代表了CRC的新治疗选择。
