THBS1+ myeloid cells expand in SLD hepatocellular carcinoma and contribute to immunosuppression and unfavorable prognosis through TREM1

Abstract

Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral or non-viral etiologies including steatotic liver diseases (SLDs). Expansion of immunosuppressive myeloid cells is a hallmark of inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance. Here, we present a high-resolution atlas of innate immune cells from patients with HCC that unravels an SLD-associated contexture characterized by influx of inflammatory and immunosuppressive myeloid cells, including a discrete population of THBS1⁺ regulatory myeloid (M_reg) cells expressing monocyte- and neutrophil-affiliated genes. THBS1⁺ M_reg cells expand in SLD-associated HCC, populate fibrotic lesions, and are associated with poor prognosis. THBS1⁺ M_reg cells are CD163⁺ but distinguished from macrophages by high expression of triggering receptor expressed on myeloid cells 1 (TREM1), which contributes to their immunosuppressive activity and promotes HCC tumor growth in vivo. Our data support myeloid subset-targeted immunotherapies to treat HCC.

Keywords: CP: Cancer; TREM1; hepatocellular carcinoma; immunotherapy; inflammation; innate immunity; liver cancer; metabolism; myeloid cells; steatohepatitis.