Blocking siglec-10hi tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma
Open accessAbstract
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 10 high(Siglec-10 hi) 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-10 hi TAMs. RNA sequencing data also revealed that numerous M2-like signaling pathways were significantly upregulated in Siglec-10 hi TAMs. High infiltration of Siglec-10 hi 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-10 hi TAMs are associated with immune suppression in the TME, and indicate poor prognosis in patients with HCC. Targeting Siglec-10 hi TAMs may serve as a promising immunotherapy approach for HCC.
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Other ICIs such as α-LAG-3, α-PVRIG, α-TIGIT, α-Siglec-10 also synergized with α-PD-1/PD-L1 in enhancing TIL function and suppressing tumor growth.
“Besides α-TIM-3, other ICIs such as α-LAG-3, α-PVRIG, α-TIGIT, α- Siglec-10 also synergized with α-PD-1/PD-L1 in enhancing TIL function and suppressing tumor growth [161–164].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [164]
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References 56 · Cited by 61
- Authors
- Xiao, N., Zhu, X., Li, K., Chen, Y., Liu, X., Xu, B., Lei, M., Xu, J., & Sun, H.-C.
- Affiliations
- Fudan University (CN)
- Qilu Hospital of Shandong University (CN)
- Shanghai Medical College of Fudan University (CN)
- Corresponding author
- Xu, Jiejie
- Sun, Hui-Chuan
- Venue
- Experimental Hematology & Oncology
- Published
- 2021-06-10
- Volume
- 10
- Issue
- 1
- Pages
- 36-36
- ISSN
- 2162-3619 (ISSN-L)
- PMC
- PMC8191104
- OpenAlex
- W3168300310
- Cited by
- 61
- References
- 56
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 13 · 2023: 20 · 2022: 8 · 2021: 3
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Experimental Hematology and Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Leading Investigator Program of the Shanghai municipal government (17XD1401100)
- National Basic Research Program of China (2015CB554005)
- National Natural Science Foundation of China (31770851, 81871928, 81672326)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- Siglec-10, tumor-associated macrophages, hepatocellular carcinoma, tumor microenvironment, immunosuppression, CD8+ T cell function, M2 macrophages, pembrolizumab, PD-1 inhibitors, immunotherapy, prognostic factors, sialic acid-binding lectins
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