Single-cell RNA sequencing reveals cell subpopulations in the tumor microenvironment contributing to hepatocellular carcinoma

Jiamin Gao; Zhijian Li; Qinchen Lu; Jialing Zhong; Lixin Pan; Chao Feng; Shaomei Tang; Xi Wang; Yuting Tao; Jianyan Lin; Qiuyan Wang

doi:10.3389/fcell.2023.1194199

Single-cell RNA sequencing reveals cell subpopulations in the tumor microenvironment contributing to hepatocellular carcinoma

Front Cell Dev Biol. 2023 Jun 2:11:1194199. doi: 10.3389/fcell.2023.1194199. eCollection 2023.

Authors

Jiamin Gao^{1

2

3}, Zhijian Li^{1

2

4}, Qinchen Lu^{1

2

5}, Jialing Zhong^{2

5}, Lixin Pan^{1

2

5}, Chao Feng^{1

2

5}, Shaomei Tang^{2

5}, Xi Wang^{2

5}, Yuting Tao^{1

2

5}, Jianyan Lin⁶, Qiuyan Wang^{1

2

5}

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China.
² Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China.
³ Laboratory of Infectious Disease, The Fourth People's Hospital of Nanning, Nanning, China.
⁴ Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
⁵ Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, China.
⁶ Administrative Office, The First People's Hospital of Nanning, Nanning, China.

Abstract

Background: Hepatocellular carcinoma (HCC) is among the deadliest cancers worldwide, and advanced HCC is difficult to treat. Identifying specific cell subpopulations in the tumor microenvironment and exploring interactions between the cells and their environment are crucial for understanding the development, prognosis, and treatment of tumors. Methods: In this study, we constructed a tumor ecological landscape of 14 patients with HCC from 43 tumor tissue samples and 14 adjacent control samples. We used bioinformatics analysis to reveal cell subpopulations with potentially specific functions in the tumor microenvironment and to explore the interactions between tumor cells and the tumor microenvironment. Results: Immune cell infiltration was evident in the tumor tissues, and BTG1 ⁺ RGS1 ⁺ central memory T cells (Tcms) interact with tumor cells through CCL5-SDC4/1 axis. HSPA1B may be associated with remodeling of the tumor ecological niche in HCC. Cancer-associated fibroblasts (CAFs) and macrophages (TAMs) were closely associated with tumor cells. APOC1 ⁺ SPP1 ⁺ TAM secretes SPP1, which binds to ITGF1 secreted by CAFs to remodel the tumor microenvironment. More interestingly, FAP ⁺ CAF interacts with naïve T cells via the CXCL12-CXCR4 axis, which may lead to resistance to immune checkpoint inhibitor therapy. Conclusion: Our study suggests the presence of tumor cells with drug-resistant potential in the HCC microenvironment. Among non-tumor cells, high NDUFA4L2 expression in fibroblasts may promote tumor progression, while high HSPA1B expression in central memory T cells may exert anti-tumor effects. In addition, the CCL5-SDC4/1 interaction between BTG1 ⁺ RGS1 ⁺ Tcms and tumor cells may promote tumor progression. Focusing on the roles of CAFs and TAMs, which are closely related to tumor cells, in tumors would be beneficial to the progress of systemic therapy research.

Keywords: cellular communication; hepatocellular carcinoma; receptor-ligand interaction; single-cell RNA sequencing; tumor microenvironment.

Grants and funding

This work was supported by the Guangxi Science and Technology Base and Talent Special Fund (AB23026002, AD22035042), National Natural Science Foundation of China (82060512, 31471271, 31560311), Guangxi Natural Science Fund for Innovation Research Team (2016GXNSFGA380006), Guangxi science and technology development project (AD17195090, AB18126055), Natural Science Foundation of Guangxi Province of China (2020GXNSFAA259022), Innovation Project of Guangxi Graduate Education (YCSW2021139), International Communication of Guangxi Medical University Graduate Education.