The immune-metabolic crosstalk between CD3+C1q+TAM and CD8+T cells associated with relapse-free survival in HCC

Yanying Yang; Lu Sun; Zhouyi Chen; Weiren Liu; Qiyue Xu; Fangming Liu; Mingyue Ma; Yuwen Chen; Yan Lu; Hao Fang; Geng Chen; Yinghong Shi; Duojiao Wu

doi:10.3389/fimmu.2023.1033497

The immune-metabolic crosstalk between CD3⁺C1q⁺TAM and CD8⁺T cells associated with relapse-free survival in HCC

Front Immunol. 2023 Feb 9:14:1033497. doi: 10.3389/fimmu.2023.1033497. eCollection 2023.

Authors

Yanying Yang^{1

2}, Lu Sun³, Zhouyi Chen³, Weiren Liu^{4

5

6}, Qiyue Xu⁷, Fangming Liu³, Mingyue Ma⁸, Yuwen Chen¹, Yan Lu⁸, Hao Fang⁹, Geng Chen⁷, Yinghong Shi^{4

5

6}, Duojiao Wu^{1

3}

Affiliations

¹ Jinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China.
² Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ Shanghai Key Laboratory of Lung Inflammation and Injury, Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China.
⁴ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Chinese Academy of Medical Sciences, Shanghai, China.
⁶ Research Unit of Bench and Clinic Research for Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Shanghai, China.
⁷ Center for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
⁸ Department of Endocrinology and Metabolism, Zhongshan Hospital, Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Fudan University, Shanghai, China.
⁹ Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.

Abstract

Introduction: Although multiple targeted treatments have appeared, hepatocellular carcinoma (HCC) is still one of the most common causes of cancer-related deaths. The immunosuppressive tumor microenvironment (TME) is a critical factor in the oncogenesis and progression of HCC. The emerging scRNA-seq makes it possible to explore the TME at a high resolution. This study was designed to reveal the immune-metabolic crosstalk between immune cells in HCC and provide novel strategies to regulate immunosuppressive TME.

Method: In this study, we performed scRNA-seq on paired tumor and peri-tumor tissues of HCC. The composition and differentiation trajectory of the immune populations in TME were portrayed. Cellphone DB was utilized to calculate interactions between the identified clusters. Besides, flow cytometry, RT-PCR and seahorse experiments were implemented to explore potential metabolic and epigenetic mechanisms of the inter-cellular interaction.

Result: A total of 19 immune cell clusters were identified and 7 were found closely related to HCC prognosis. Besides, differentiation trajectories of T cells were also presented. Moreover, a new population, CD3+C1q+ tumor-associated macrophages (TAM) were identified and found significantly interacted with CD8+ CCL4+T cells. Compared to the peri-tumor tissue, their interaction was attenuated in tumor. Additionally, the dynamic presence of this newly found cluster was also verified in the peripheral blood of patients with sepsis. Furthermore, we found that CD3+C1q+TAM affected T cell immunity through C1q signaling-induced metabolic and epigenetic reprogramming, thereby potentially affecting tumor prognosis.

Conclusion: Our study revealed the interaction between CD3+C1q+TAM and CD8+ CCL4+T cells and may provide implications for tackling the immunosuppressive TME in HCC.

Keywords: C1q; HCC; T cell; immunometabolism; tumor-associated macrophage.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD3 Complex / immunology
CD8-Positive T-Lymphocytes
Carcinoma, Hepatocellular*
Chronic Disease
Complement C1q / metabolism
Humans
Liver Neoplasms*
Neoplasm Recurrence, Local / pathology
Tumor Microenvironment
Tumor-Associated Macrophages / metabolism

Substances

Complement C1q
CD3 Complex

Grants and funding

This study was supported by the National Natural Science Foundation of China (No.81771672), “Cross key project of mathematics and medical health” of the National Natural Science Foundation of China (No.12026608), Open fund project of Shenzhen BGI Institute of Life Science(No.BGIRSZ20200004) and Special Fund for Clinical Research of Zhongshan Hospital, Fudan University (No.2020ZSLC07), Key Subject Construction Program of Shanghai Health Administrative Authority (ZK2019B30), and Shanghai Engineering Research Center of Tumor Multi-Target Gene Diagnosis (20DZ2254300). The funding agencies had no role in the study’s design and conduct, collecting, analyzing, and interpreting the data or preparation.