IL11 organizes a macrotrabecular structure with immune evasion in aggressive hepatocellular carcinoma

BACKGROUND & AIMS: Molecular characteristics and tumor microenvironment of aggressive hepatocellular carcinoma (HCC) remains uncertain, and therapeutic strategies effective for aggressive HCC have not been determined. We have established a syngeneic mouse model of aggressive HCC to elucidate therapeutic targets. METHODS: A mouse HCC model was generated from 3H3, a hepatoma cell line of C57BL/6 mouse origin, following Trp53 knockout and MYC overexpression (3H3PM), which are major genetic alterations in aggressive human HCC. Immunohistochemical analysis of 104 human HCC tissues was performed for validation. RESULTS: The 3H3PM cells demonstrated abnormal cell cycle regulation, and exhibited highly tumorigenic and metastatic phenotypes in immunocompetent C57BL/6 mice. The histological features of the grafted tumors were similar to those of aggressive human HCC; a predominant macrotrabecular pattern and a distinctive structure of cell clusters surrounded by endothelial cells, namely macrotrabecular-massive (MTM) HCC and vessels encapsulating tumor clusters (VETC), as well as T cell depletion. Gene expression analysis indicated that interleukin-11 (IL11) was specifically upregulated in aggressive mouse and human HCC, and Il11 knockout (Il11-KO) disrupted the MTM/VETC structure and recruited T cells in the 3H3PM tumors. Treatment with anti-PD-1 antibody successfully eliminated tumors of the Il11-KO 3H3PM cells, but not the 3H3PM cells alone. CONCLUSION: We created a syngeneic mouse model recapitulating aggressive human HCC with the MTM/VETC structure and the immune-suppressive microenvironment by Trp53 knockout and MYC overexpression. IL11 contributed to MTM/VETC formation and T cell exclusion in the aggressive HCC phenotype, and the combination of IL11 inhibition and immune checkpoint blockade may act in synergy to promote anti-tumor effects in aggressive HCC.