1. Blocking siglec-10hi tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma
- Author
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Nan Xiao, Jiejie Xu, Hui-Chuan Sun, Bin Xu, Kangshuai Li, Xiao-Dong Zhu, Yifan Chen, Xue-Feng Liu, and Ming Lei
- Subjects
0301 basic medicine ,Cancer Research ,Hepatocellular carcinoma ,medicine.medical_treatment ,T cell ,Pembrolizumab ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cytotoxic T cell ,Medicine ,Diseases of the blood and blood-forming organs ,RC254-282 ,Tumor microenvironment ,business.industry ,Immune evasion ,Macrophages ,SIGLEC ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Hematology ,Immunotherapy ,respiratory system ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,RC633-647.5 ,business ,CD8 - Abstract
BackgroundTumor-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.MethodsHCC 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.ResultsOur 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-10hiTAMs. RNA sequencing data also revealed that numerous M2-like signaling pathways were significantly upregulated in Siglec-10hiTAMs. High infiltration of Siglec-10hiTAMs 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.ConclusionsSiglec-10hiTAMs are associated with immune suppression in the TME, and indicate poor prognosis in patients with HCC. Targeting Siglec-10hiTAMs may serve as a promising immunotherapy approach for HCC.
- Published
- 2021