Nan Xiao1,2, Xiaodong Zhu1,2, Kangshuai Li3, Yifan Chen4, Xuefeng Liu1,2, Bin Xu1,2, Ming Lei1,2, Jiejie Xu5, Hui-Chuan Sun6,7. 1. Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China. 2. Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China. 3. Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China. 4. Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China. 5. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. jjxufdu@fudan.edu.cn. 6. Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China. sun.huichuan@zs-hospital.sh.cn. 7. Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China. sun.huichuan@zs-hospital.sh.cn.
Abstract
BACKGROUND: Tumor-associated macrophages (TAMs) promote key processes in the modulation of tumor microenvironment (TME). However, the clinical significance of heterogeneous subpopulations of TAMs in hepatocellular carcinoma (HCC) remains unknown. METHODS: HCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas were obtained and analyzed. Immunohistochemistry and flow cytometry were performed to detect the characteristics of sialic acid-binding immunoglobulin-like lectin 10high (Siglec-10hi) TAMs and explore their impact on the TME of HCC. The effect of Siglec-10 blockade was evaluated in vitro based on fresh human tumor tissues. RESULTS: Our data revealed that Siglec-10 was abundant in a large proportion of HCC specimens and prominently distributed on macrophages. Kaplan-Meier curves and Cox regression analysis showed that intratumoral Siglec-10+ cell enrichment was associated with unfavorable prognosis in patients with HCC. Notably, multiple anti-inflammatory cytokines and inhibitory receptors were enriched in Siglec-10hi TAMs. RNA sequencing data also revealed that numerous M2-like signaling pathways were significantly upregulated in Siglec-10hi TAMs. High infiltration of Siglec-10hi TAMs was associated with impaired CD8+ T cell function in HCC. Of note, blocking Siglec-10 with the competitive binding antibody Siglec-10 Fc led to decreased expression of immunosuppressive molecules and increased the cytotoxic effects of CD8+ T cells against HCC cells. Moreover, blocking Siglec-10 promoted the anti-tumor efficacy of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab. CONCLUSIONS: Siglec-10hi TAMs are associated with immune suppression in the TME, and indicate poor prognosis in patients with HCC. Targeting Siglec-10hi TAMs may serve as a promising immunotherapy approach for HCC.
BACKGROUND:Tumor-associated macrophages (TAMs) promote key processes in the modulation of tumor microenvironment (TME). However, the clinical significance of heterogeneous subpopulations of TAMs in hepatocellular carcinoma (HCC) remains unknown. METHODS:HCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas were obtained and analyzed. Immunohistochemistry and flow cytometry were performed to detect the characteristics of sialic acid-binding immunoglobulin-like lectin 10high (Siglec-10hi) TAMs and explore their impact on the TME of HCC. The effect of Siglec-10 blockade was evaluated in vitro based on fresh humantumor tissues. RESULTS: Our data revealed that Siglec-10 was abundant in a large proportion of HCC specimens and prominently distributed on macrophages. Kaplan-Meier curves and Cox regression analysis showed that intratumoral Siglec-10+ cell enrichment was associated with unfavorable prognosis in patients with HCC. Notably, multiple anti-inflammatory cytokines and inhibitory receptors were enriched in Siglec-10hi TAMs. RNA sequencing data also revealed that numerous M2-like signaling pathways were significantly upregulated in Siglec-10hi TAMs. High infiltration of Siglec-10hi TAMs was associated with impaired CD8+ T cell function in HCC. Of note, blocking Siglec-10 with the competitive binding antibody Siglec-10 Fc led to decreased expression of immunosuppressive molecules and increased the cytotoxic effects of CD8+ T cells against HCC cells. Moreover, blocking Siglec-10 promoted the anti-tumor efficacy of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab. CONCLUSIONS:Siglec-10hi TAMs are associated with immune suppression in the TME, and indicate poor prognosis in patients with HCC. Targeting Siglec-10hi TAMs may serve as a promising immunotherapy approach for HCC.
Authors: Amira A Barkal; Rachel E Brewer; Maxim Markovic; Mark Kowarsky; Sammy A Barkal; Balyn W Zaro; Venkatesh Krishnan; Jason Hatakeyama; Oliver Dorigo; Layla J Barkal; Irving L Weissman Journal: Nature Date: 2019-07-31 Impact factor: 49.962