Macrophage-coated tumor cluster aggravates hepatoma invasion and immunotherapy resistance via generating local immune deprivation

• Published in: Cell reports. Medicine Vol. 5; no. 5; p. 101505
• Main Authors: Ning, Junya, Ye, Yingnan, Shen, Hongru, Zhang, Runjiao, Li, Huikai, Song, Tianqiang, Zhang, Rui, Liu, Pengpeng, Chen, Guidong, Wang, Hailong, Zang, Fenglin, Li, Xiangchun, Yu, Jinpu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.05.2024; Elsevier
• Subjects: Animals; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Female; hepatocellular carcinoma; Humans; immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; immunological evasion; Immunotherapy - methods; Liver Neoplasms - immunology; Liver Neoplasms - pathology; M2BP; Macrophages - immunology; macrophages coated tumor cluster; Male; Mice; Middle Aged; Neoplasm Invasiveness; T cell exclusion; T-Lymphocytes, Cytotoxic - immunology; Tumor Microenvironment - immunology; tumor-associated macrophages; Tumor-Associated Macrophages - immunology; macrophages coated tumor cluster; M2BP; immunological evasion; immune checkpoint inhibitors; hepatocellular carcinoma; tumor-associated macrophages; T cell exclusion
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101505

Immune checkpoint inhibitors (ICIs) represent a promising treatment for hepatocellular carcinoma (HCC) due to their capacity for abundant lymphocyte infiltration. However, some patients with HCC respond poorly to ICI therapy due to the presence of various immunosuppressive factors in the tumor microenvironment. Our research reveals that a macrophage-coated tumor cluster (MCTC) signifies a unique spatial structural organization in HCC correlating with diminished recurrence-free survival and overall survival in a total of 572 HCC cases from 3 internal cohorts and 2 independent external validation cohorts. Mechanistically, tumor-derived macrophage-associated lectin Mac-2 binding protein (M2BP) induces MCTC formation and traps immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cell exclusion and local immune deprivation. Blocking M2BP with a Mac-2 antagonist might provide an effective approach to prevent MCTC formation, enhance T cell infiltration, and thereby improve the efficacy of ICI therapy in HCC. [Display omitted] •MCTC structure serves as a biomarker for poor prognosis and ICI resistance in HCC•MCTC+ HCC: Immunologically hot tumors with immune cells trapped outside tumor cells•Macrophages in MCTC+ HCC exhibit a distinct immunosuppressive phenotype•Anti-PD-1 and GB1107 therapy inhibits MCTC+ HCC growth and metastasis Ning et al. identify that the MCTC structure serves as a biomarker for poor prognosis and ICI resistance in HCC, functioning by sequestering cytotoxic T cells and establishing an immunosuppressive niche. Their strategy disrupts MCTC formation by targeting M2BP, restoring T cell infiltration and potentially boosting ICI treatment efficacy.