Transcriptomics

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Immunosuppressive inflammation driven by LPS/TLR4 signalling in hepatocellular carcinoma with low immune cell infiltration


ABSTRACT: Non-inflamed liver tumors (i.e. immunologically silent and desert phenotype) account for two-thirds of hepatocellular carcinomas (HCC) and represent a major challenge for immune-based cancer therapies. Elucidating the factors behind the lack of T cell response would enable us to define an appropriate therapy to induce antitumor immunity based on tumor immunobiology. We applied unsupervised machine learning to the transcriptome of a rigorously selected set of non- or poorly infiltrated HCC, identified independent modular components and explored their characteristics through gene enrichment analysis and integration of molecular, cytometric, immunohistochemical and clinicopathological data. Here we demonstrate that non-/poorly infiltrated HCC (referred to as cold HCC) exhibits intricate, multi-layered mechanisms by which tumors evade the immune response. These include the recruitment of immunosuppres-sive myeloid cells into the tumor microenvironment (TME) in relation to tumor richness in Gram-negative bacterial lipopolysaccharide (LPS) and activation of the LPS/TLR4 signaling pathway. LPS-containing cold HCCs undergo immunosuppressive inflammation, likely via activation of the EGFR, LPS/TLR4 and NFKB signaling pathways. This is associated with increased expression of the checkpoint inhibitor TIM3 and its ligand, galectin 9 (Gal9). All the immune evasion factors detected in cold HCC are also at play in infiltrated HCC, suggesting in the latter the presence of TME regulatory signals opposing them. This study highlights mechanisms of immune tolerance in non-infiltrated HCC and supports the role of tumor ex-trinsic mechanisms in regulating tumor immunity in HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248516 | GEO | 2024/11/20

REPOSITORIES: GEO

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