Spatial proteomics of immune microenvironment in nonalcoholic steatohepatitis-associated hepatocellular carcinoma

• Main Authors: Li, Meiyi, Wang, Lina, Cong, Liang, Wong, Chi Chun, Zhang, Xiang, Chen, Huarong, Zeng, Tao, Li, Bin, Jia, Xian, Huo, Jihui, Huang, Yuhua, Ren, Xiaoxue, Peng, Sui, Fu, Guo, Xu, Lixia, Sung, Joseph Jao Yiu, Kuang, Ming, Li, Xiaoxing, Yu, Jun
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2024
• Subjects: Medicine, Health and Life Sciences; Liver tumor; Hepatocellular
• Online Access: https://hdl.handle.net/10356/180080
• Institution: Nanyang Technological University

Background and Aims: NASH-HCC is inherently resistant to immune checkpoint blockade, but its tumor immune microenvironment is largely unknown. Approach and Results: We applied the imaging mass cytometry to construct a spatially resolved single-cell atlas from the formalin-fixed and paraffin-embedded tissue sections from patients with NASH-HCC, virus-HCC (HBV-HCC and HCV-HCC), and healthy donors. Based on 35 biomarkers, over 750,000 individual cells were categorized into 13 distinct cell types, together with the expression of key immune functional markers. Higher infiltration of T cells, myeloid-derived suppressor cell (MDSCs), and tumor-Associated macrophages (TAMs) in HCC compared to controls. The distribution of immune cells in NASH-HCC is spatially heterogeneous, enriched at adjacent normal tissues and declined toward tumors. Cell-cell connections analysis revealed the interplay of MDSCs and TAMs with CD8+T cells in NASH-HCC. In particular, exhausted programmed cell death 1 (PD-1+)CD8+T cells connected with programmed cell death-ligand 1 (PD-L1+)/inducible T cell costimulator (ICOS+) MDSCs and TAMs in NASH-HCC, but not in viral HCC. In contrast, CD4+/CD8+T cells with granzyme B positivity were reduced in NASH-HCC. Tumor cells expressed low PD-L1 and showed few connections with immune cells. Conclusions: Our work provides the first detailed spatial map of single-cell phenotypes and multicellular connections in NASH-HCC. We demonstrate that interactions between MDSCs and TAMs with effector T cells underlie immunosuppression in NASH-HCC and are an actionable target.