TREM1 ⁺ regulatory myeloid cells expand in steatohepatitis-HCC and associate with poor prognosis and therapeutic resistance to immune checkpoint blockade

ABSTRACT Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral and non-viral etiologies. Immune checkpoint blockade primarily benefits patients with viral HCC. Expansion of suppressive myeloid cells is a hallmark of chronic inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance in the steatohepatitis setting. Here, we present a high resolution atlas of hepatic innate immune cells from patients with HCC that unravels a steatohepatitis contexture characterized by the emergence of high entropy myeloid cell states and myeloid-biased NK cell differentiation. We identify a discrete population of tumor-infiltrating myeloid cells, predominant in the steatohepatitis setting, that expresses a variety of myeloid lineage-affiliated genes, including granulocyte, macrophage and dendritic cell features, and can be identified in HCC tumors based on selective dual expression of TREM1 and CD163 . Functional characterization reveals that TREM1 + CD163 + myeloid cells highly express TGFβ and IL-13RA, localize to HCC fibrotic lesions, and potently suppress T cell effector functions ex vivo , a function further potentiated by TREM1 engagement. We refer to this population as TREM1 + CD163 + regulatory myeloid cells (TREM1 + CD163 + M reg ). Deconvolution analyses in large cohorts of patients with HCC and other solid tumors reveals that the density of TREM1 + CD163 + M reg increases in advanced stages, associates with poor prognosis, and therapeutic resistance to PD-1 blockade. Our data support myeloid subset-targeted immunotherapies to treat HCC and identify TREM1 as a therapeutic target. HIGHLIGHTS Atlas of hepatic innate immune cells (100,000 transcriptomes) from patients with HCC Core signatures to identify, discriminate and localize innate lymphoid and myeloid cells A population of TREM1 + CD163 + myeloid cells, referred to as TREM1 + CD163 + M reg , expands in steatohepatitis HCC TREM1 + CD163 + M reg express granulocyte- and macrophage/dendritic cell-lineage genes TREM1 + CD163 + M reg potently suppress T cell effector functions, which is potentiated by TREM1 engagement by cognate ligands TREM1 + CD163 + M reg produce high levels of TGFβ and populate fibrotic lesions The density of TREM1 + CD163 + M reg increases in advanced HCC and associate with poor patient survival The density of TREM1 + CD163 + M reg associates with resistance to immune checkpoint blockade in other solid tumors

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