Macrophages Coated Tumor Cluster (MCTC) Aggravated Hepatoma Invasion and Immunotherapy Resistance via Entrapping Cytotoxic T Cells to Generate Local Immune Deprivation in a M2BP-dependent manner
Immune checkpoint inhibitors (ICIs) represent promising treatment for hepatocellular carcinoma (HCC) due to abundant lymphocyte infiltration. However, some HCC patients respond poorly to ICI therapy due to the presence of various immunosuppressive factors in tumor microenvironment. Our research revealed that macrophage-coated tumor clusters (MCTCs) signified a unique spatial structural organization in HCC, correlating with diminished recurrence-free survival (RFS) and overall survival (OS) in a total of 572 HCC cases from 3 internal cohorts and 2 external validation cohort independently. Mechanistically, Tumor-derived M2BP induced MCTCs formation, and entrapped immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cells exclusion and local immune deprivation. Combined treatment of anti-PD-1 antibody and Mac-2 antagonist GB1107 before MCTC formation could significantly attenuated HCC growth and inhibited HCC metastasis in vivo by recovering intratumoral infiltration of cytotoxic T cells, offering a potential strategy to enhance ICI efficacy in HCC. Overall design: we employed single-cell RNA sequencing to analyze tissues from 3 MCTC+ and 3 MCTC¯ cases.