Dataset Information

SIRT5 loss promotes hepatocarcinogenesis via bile acid-induced immunosuppressive microenvironment

ABSTRACT: Hepatocellular carcinoma (HCC) is a prototypical inflammation-associated cancer and the tumor microenvironment (TME) plays a pivotal role in HCC pathogenesis and response to therapy. The liver is a metabolically active organ, but how liver metabolism impacts TME during HCC development and response to immunotherapy are poorly understood. Here, we show that the metabolic regulator SIRT5 is downregulated in human primary HCC samples, and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, which is due to hypersuccinylation and increased BA biosynthesis in the peroxisome. BA acts as a cell-signaling mediator to stimulate its nuclear receptor and promotes M2-like macrophage polarization, thereby creating an immunosuppressive microenvironment favorable for HCC initiating cells. Furthermore, high serum taurocholic acid, a major primary BA, correlates with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in liver tissue samples from HCC patients. Importantly, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency on promoting M2-like polarized TAMs and liver tumor growth. Our study thus uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC. These results also suggest a potential strategy using clinically proven bile acid sequestrants for the treatment of HCC patients, especially those with decreased SIRT5 and abnormally high BAs.

ORGANISM(S): Mus musculus

PROVIDER: GSE193213 | GEO | 2022/01/10

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) which can either promote tumor progression (M2) or induce antitumor immunity (M1). The hypothesis of our study is that the expression of FOLR2 is associated with an M2-like macrophage profile. The main goal of this study is to compare the transcriptomic profile of FOLR2 positive and FOLR2 negative TAMs obtained from the ascites of C57BL/6 mice bearing ovarian ID8 intraperitoneal tumors. Abstract: The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Selective targeting of the pro-tumorigenic subset of TAMs represents an attractive therapeutic strategy. Here, we demonstrate that a subset of TAMs that expressing folate receptor β (FRβ) possess an immunosuppressive, tumor-promoting M2-like profile, while FRβ negative TAMs feature pro-inflammatory M1 macrophage properties. In syngeneic tumor mouse models, the administration of FRβ-targeted chimeric antigen receptor (CAR) T-cells mediated elimination of FRβ+ TAMs in the TME, which resulted in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8+ T-cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR T-cells also improved the effectiveness of tumor-directed anti-mesothelin CAR T-cells, while simultaneous co-administration of both CAR products did not. Thus, CAR T-cell-mediated depletion of immunosuppressive M2-like TAMs incites a pro-inflammatory TME that broadens endogenous antitumor immunity and limits tumor progression, highlighting the pro-tumor role of FRβ+ TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.

Dataset Information

SIRT5 loss promotes hepatocarcinogenesis via bile acid-induced immunosuppressive microenvironment

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure