Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma.
Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma.
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癌症相关成纤维细胞通过 IL6-STAT3 途径诱导 PDL1 中性粒细胞，从而促进肝细胞癌的免疫抑制
DOI：
10.1038/s41419-018-0458-4
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发表时间：
2018-04-01
影响因子：
9
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Cheng Y;Li H;Deng Y;Tai Y;Zeng K;Zhang Y;Liu W;Zhang Q;Yang Y
新出现的证据表明，癌症相关成纤维细胞（CAF）通过重塑肿瘤微环境来影响肿瘤进展。中性粒细胞是实体瘤的主要成分，在癌症进展中很重要。肝细胞癌（HCC）中中性粒细胞的表型和功能是否受CAFs的影响尚不清楚。在此，我们研究了HCC衍生的CAFs（HCC-CAFs）对中性粒细胞的影响，并探讨了这种影响的生物学作用。我们发现，HCC-CAFs诱导中性粒细胞的趋化性，并保护他们免受自发性凋亡。嗜中性粒细胞被来自HCC-CAF的条件培养基激活，其中CD 66 b、PDL 1、IL 8、TNF α和CCL 2的表达增加，而CD 62 L的表达降低。HCC-CAF致敏的中性粒细胞通过PD 1/PDL 1信号通路损害T细胞功能。我们发现，HCC-CAFs诱导中性粒细胞中STAT 3通路的激活，这对活化的中性粒细胞的存活和功能至关重要。此外，我们证明了HCC-CAF衍生的IL 6负责中性粒细胞的STAT 3活化。总的来说，我们的研究结果表明，HCC-CAFs通过IL 6-STAT 3-PDL 1信号级联调节HCC内中性粒细胞的存活、活化和功能，这为CAFs在重塑癌症生态位中的作用提供了一种新的机制，并为HCC治疗提供了一个潜在的靶点。
Emerging evidence indicate that cancer-associated fibroblasts (CAFs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are prominent components of solid tumors and important in cancer progression. Whether the phenotype and function of neutrophils in hepatocellular carcinoma (HCC) are influenced by CAFs is not well understood. Herein, we investigated the effect of HCC-derived CAFs (HCC-CAFs) on the neutrophils and explored the biological role of this effect. We found that HCC-CAFs induced chemotaxis of neutrophils and protected them from spontaneous apoptosis. Neutrophils were activated by the conditioned medium from HCC-CAFs with increased expression of CD66b, PDL1, IL8, TNFa, and CCL2, and with decreased expression of CD62L. HCC-CAF-primed neutrophils impaired T-cell function through the PD1/PDL1 signaling pathway. We revealed that HCC-CAFs induced the activation of STAT3 pathways in neutrophils, which are essential for the survival and function of activated neutrophils. In addition, we demonstrated that HCC-CAF-derived IL6 was responsible for the STAT3 activation of neutrophils. Collectively, our results suggest that HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6–STAT3–PDL1 signaling cascade, which presents a novel mechanism for the role of CAFs in remodeling the cancer niche and provides a potential target for HCC therapy.
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