Kaposi's sarcoma-associated herpesvirus infection promotes differentiation and polarization of monocytes into tumor-associated macrophages

Tumor associated macrophages (TAMs) promote angiogenesis, tumor invasion and metastasis, and suppression of anti-tumor immunity. These myeloid cells originate from monocytes, which differentiate into TAMs upon exposure to the local tumor microenvironment. We previously reported that Kaposi's sarcoma-associated herpes virus (KSHV) infection of endothelial cells induces the cytokine angiopoietin-2 (Ang-2) to promote migration of monocytes into tumors. Here we report that KSHV infection of endothelial cells induces additional cytokines including interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-13 (IL-13) that drive monocytes to differentiate and polarize into TAMs. The KSHV-induced TAMs not only express TAM-specific markers such as CD-163 and legumain (LGMN) but also display a gene expression profile with characteristic features of viral infection. More importantly, KSHV-induced TAMs enhance tumor growth in nude mice. These results are consistent with the strong presence of TAMs in Kaposi's sarcoma (KS) tumors. Therefore, KSHV infection of endothelial cells generates a local microenvironment that not only promotes the recruitment of monocytes but also induces their differentiation and polarization into TAMs. These findings reveal a new mechanism of KSHV contribution to KS tumor development.

肿瘤相关巨噬细胞（Tumor associated macrophages, TAMs）可促进血管生成、肿瘤侵袭与转移，并抑制抗肿瘤免疫应答。这类髓系细胞起源于单核细胞，在局部肿瘤微环境的作用下可分化为TAMs。本课题组此前研究发现，内皮细胞感染卡波西肉瘤相关疱疹病毒（Kaposi's sarcoma-associated herpes virus, KSHV）可诱导细胞因子血管生成素-2（angiopoietin-2, Ang-2）的表达，进而促进单核细胞向肿瘤组织募集。本研究证实，内皮细胞感染KSHV还可诱导白细胞介素-6（interleukin-6, IL-6）、白细胞介素-10（interleukin-10, IL-10）及白细胞介素-13（interleukin-13, IL-13）等多种细胞因子的产生，这些细胞因子可驱动单核细胞分化并极化为TAMs。KSHV诱导产生的TAMs不仅表达CD163、legumain（LGMN）等TAM特异性标志物，还呈现出带有病毒感染特征的基因表达谱。更为关键的是，KSHV诱导的TAMs可促进裸小鼠体内的肿瘤生长。上述结果与卡波西肉瘤（Kaposi's sarcoma, KS）组织中TAMs大量浸润的现象相符。综上，内皮细胞感染KSHV所构建的局部微环境，不仅可促进单核细胞向肿瘤组织募集，还可诱导单核细胞分化并极化为TAMs。本研究揭示了KSHV促进KS肿瘤发生发展的全新分子机制。