Abstract 1050: Serum interleukin-27 serves as an early biomarker predicting development of hepatocellular carcinoma (HCC) in two large prospective cohorts
Authors: Yuan Jian-Min , Yue Wang , Wang Renwei , Admas-Haduch Jennifer , Koh Woon-Puay , Gao Yu-Tang , Lotze Michael T. 
Published: September 2020

Abstract
Background: Interleukin-27 (IL-27), which consists of p28 and Epstein-Barr virus induced gene 3 (EBI3) subunits, is a heterodimeric member of the IL-12/IL-23 cytokine family. Overexpression of IL-27 increases T cell expression of inhibitory receptors including PD-1, LAG3, TIGIT, and TIM3 that could limit intensity and duration of T cell responses to infection and cancer. IL-27 is overexpressed in HCC. The purpose of the study was to examine the role of IL-27 in the development of HCC in humans.
Methods: Two parallel studies were conducted. The discovery study included 100 HCC cases and 100 individually matched controls from the Singapore Chinese Health Study, which enrolled 32,000 participants with blood samples free of cancer at entry into the study and subsequently followed up for &gt;15 years. The validation study also included 100 HCC cases and 100 matched controls from the Shanghai Cohort Study, a prospective cohort of 18,000 participants who were free of cancer at entry and similarly followed up for &gt;20 years. Human IL-27 protein was quantified in sera that were collected, on average, 4.5 year prior to the diagnosis of HCC. Conditional logistic regression method was used to estimate odds ratio (OR) and 95% confidence interval (CI) of HCC for higher tertiles of IL-27 with adjustment for hepatitis B surface antigen (HBsAg), alcohol intake, body mass index and cigarette smoking. The Cancer Genome Atlas (TCGA) data were analyzed for the IL-27 gene expression in liver and other cancers.
Results: Serum IL-27 levels were significantly higher in persons who subsequently developed HCC than controls who remained free of HCC in both studies. In the discovery study, persons in the 2nd (1.39-1.95 ng/mL) and 3rd tertile of IL-27 (&gt;1.95 ng/ml) had 9.3 (95% CI = 1.07-80.36) and 51.7 (95% CI = 5.1-527.8) times the risk of developing HCC, respectively, compared with the lowest IL-27 (&lt;1.39 ng/ml). These novel results were confirmed in the validation study; the corresponding ORs (95% CIs) for HCC were 4.9 (1.2-19.6) and 16.3 (3.5-77.4) (both Ptrend &lt; 0.001). When IL-27 and HBsAg were jointly analyzed, the OR (95% CI) of HCC was 24.73 (3.23-189.09) for lowest IL-27 & positive HBsAg, 45.52 (8.71-237.91) for highest IL-27 & negative HBsAg, and 265.19 (40.69-1728.45) for highest IL-27 & positive HBsAg, compared with lowest IL-27 & negative HBsAg. The TCGA analysis revealed that the IL-27 mRNA levels in primary liver cancer was at least 20 times higher than that of any other cancer.
Conclusion: Higher serum levels of IL-27 are associated with significantly higher risk of HCC development.
Implications: IL-27 can be further developed as a biomarker for identification of individuals at high risk for HCC and for diagnosis of HCC at an early stage, enabling more frequent surveillance. Anti-IL-27 agents may be developed for primary prevention of HCC. The blockade of IL-27 alone or in combination with other anti-immunosuppressive agents such as anti-PD1, anti-PD-L1, IL-2 and anti-LAG3 may represent novel immunotherapy strategies for HCC.
Citation Format: Jian-Min Yuan, Wang Yue, Renwei Wang, Jennifer Admas-Haduch, Woon-Puay Koh, Yu-Tang Gao, Michael T. Lotze. Serum interleukin-27 serves as an early biomarker predicting development of hepatocellular carcinoma (HCC) in two large prospective cohorts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1050.