IL27 Signaling Serves as an Immunologic Checkpoint for Innate Cytotoxic Cells to Promote Hepatocellular Carcinoma

Abstract

Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig­naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. Significance: HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease.

High level of HDGF expression in hepatocellular carcinoma: a potential therapeutic target associated with prognosis and immune infiltration

“…Additionally, we found that the HDGF had a signi cant negative correlation with Cytotoxic and pDC in ltration in these tissues. These observations were signi cant as both cytotoxic and pDC cells are critical to both the antitumor response and [26,27] OS in HCC [28,29]. Interestingly however, the correlation between HDGF and Th2 cell in ltration was positive, suggesting that these cells may be linked to HCC progression potentially via their M2 macrophage recruitment and polarization as well as their immunosuppressive effects within the TIME [30].…”

Healthy Sleep Patterns, Genetic Susceptibility, and Incident of Cirrhosis and Liver Cancer

“…Second, poor sleep quality can partly contribute to the alteration in serum levels of inflammatory markers, such as the accumulation of interleukin and tumor necrosis factor-α [23,24] . Interleukin-27 receptor (IL-27R) signaling was proven that it promoted liver cancer development in vivo [25] . Furthermore, prospective studies indicated that both too short and too long sleep duration were associated with a significantly high risk of type 2 diabetes [26] , which were also solid risk factors for liver cancer in patients with liver disease validated by both cohort and case-control study [27,28] .…”

Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma

“…These results suggest that IL-27 might have a role as a predictive biomarker of immunotherapy for HCC. Turan Aghayev et al also reported that elevated IL27RA mRNA expression correlated with poor survival since the treatment in Korean, Chinese, and TCGA HCC cohorts [128].…”