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

  • Cell Rep Med. 2024 Apr 9:101505. doi: 10.1016/j.xcrm.2024.101505.
Junya Ning  1 ,  Yingnan Ye  2 ,  Hongru Shen  3 ,  Runjiao Zhang  4 ,  Huikai Li  5 ,  Tianqiang Song  5 ,  Rui Zhang  4 ,  Pengpeng Liu  4 ,  Guidong Chen  4 ,  Hailong Wang  6 ,  Fenglin Zang  7 ,  Xiangchun Li  8 ,  Jinpu Yu  9
Affiliations
  • 1. Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Department of Thyroid and Breast Surgery, Tianjin Union Medical Center, Tianjin 300121, China.
  • 2. Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Clinical Laboratory, TEDA International Cardiovascular Hospital, Tianjin 300457, China.
  • 3. Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Tianjin Cancer Institute, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China.
  • 4. Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
  • 5. Department of Liver Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
  • 6. Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
  • 7. Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
  • 8. Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Tianjin Cancer Institute, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China. Electronic address: [email protected].
  • 9. Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: [email protected].
PMID: 38614095 DOI: 10.1016/j.xcrm.2024.101505
Abstract

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.

Keywords
M2BP; T cell exclusion; hepatocellular carcinoma; immune checkpoint inhibitors; immunological evasion; macrophages coated tumor cluster; tumor-associated macrophages.
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