Blanc, J.-F. | bioRxiv Science

bioRxiv2025

Proteomic profiling of advanced hepatocellular carcinoma identifies predictive signatures of response to treatments

PurposeHepatocellular carcinoma (HCC) is the most common form of liver cancer with a bad prognosis in case of advanced HCC, only eligible for palliative systemic therapies. After a decade of exclusive sorafenib monotherapy, with a response rate of <10%, the advent of immunotherapies represents a revolution in HCC. The combination of atezolizumab/bevacizumab is recommended as the first-line systemic treatment, with a response rate around 30%. However, there are currently no predictive factors for response to these treatment options. Experimental DesignWe profiled, by high-resolution mass spectrometry-based proteomics combined with machine learning analysis, a selected cohort of fixed biopsies of advanced HCC. We grouped subjects according to their objective response to treatments, corresponded to a tumor regression vs tumor progression at 4 months after treatment. ResultsWe generated a proteome database of 50 selected HCC samples. We compared the relative protein abundance between tumoral and non-tumoral liver tissues from advanced HCC patients treated. The clear distinction of these two groups for each treatment is based on deregulation for 141 protein or 87 for atezolizumab/bevacizumab and sorafenib treatment, respectively. These specific proteomic signatures were sufficient to predict the response to treatment, and revealed biological pathways involved in treatments resistance. Particularly, we validated a shift in tumor cell metabolism with an immunosuppressive environment involved in the resistance to atezolizumab/bevacizumab combination. ConclusionsWe performed an in-depth analysis of quantitative proteomic data from HCC biopsies to predict the treatment response to advanced HCC giving the ability to optimize patient management.

cancer biology↗

bioRxiv2022

TREM1+ regulatory myeloid cells expand in steatohepatitis-HCC and associate with poor prognosis and therapeutic resistance to anti-PD-1 blockade

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 TGF{beta} 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+ Mreg). Deconvolution analyses in large cohorts of patients with HCC and other solid tumors reveals that the density of TREM1+ CD163+ Mreg 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. HIGHLIGHTSO_LIAtlas of hepatic innate immune cells (100,000 transcriptomes) from patients with HCC C_LIO_LICore signatures to identify, discriminate and localize innate lymphoid and myeloid cells C_LIO_LIA population of TREM1+CD163+ myeloid cells, referred to as TREM1+CD163+ Mreg, expands in steatohepatitis HCC C_LIO_LITREM1+CD163+ Mreg express granulocyte- and macrophage/dendritic cell-lineage genes C_LIO_LITREM1+CD163+ Mreg potently suppress T cell effector functions, which is potentiated by TREM1 engagement by cognate ligands C_LIO_LITREM1+CD163+ Mreg produce high levels of TGF{beta} and populate fibrotic lesions C_LIO_LIThe density of TREM1+CD163+ Mreg increases in advanced HCC and associate with poor patient survival C_LIO_LIThe density of TREM1+CD163+ Mreg associates with resistance to immune checkpoint blockade in other solid tumors C_LI

immunology↗