Abstract 3015: Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore
Authors: Thomas Claire E. , Adibi Jennifer J. , Kuipers Allison L. , Diergaarde Brenda , Luu Hung N. , Jin Aizhen , Koh Woon-Puay , Gao Yu-Tang , Adams-Haduch Jennifer , Wang Renwei , Lokshin Anna , Behari Jaideep , Yuan Jian-Min 
Published: April 2023

Abstract
Background: Chronic inflammation plays a significant role in hepatocellular carcinoma (HCC). With rising incidence and poor prognosis of HCC, identifying relatively less invasive biomarkers, especially inflammatory ones, may improve the assessment and stratification of HCC risk. The objective of our studies was to assess if CD8+ T cell cytokines in pre-diagnostic serum are associated with risk of HCC development.
Methods: We conducted two parallel case-control studies of HCC nested within the Shanghai Cohort Study (SCS) and the Singapore Chinese Health Study (SCHS), two prospective cohorts of 81,000 individuals with 25+ years of follow-up. The serum concentrations of five CD8+ T cell cytokines ─ soluble CD137 (sCD137), soluble Fas (sFas), perforin, macrophage inflammatory protein 1-beta (MIP-1β), and tumor necrosis factor alpha (TNF-α) ─ were determined using Luminex bead-based immunoassay on 315 HCC cases and 315 individually matched controls in the SCS, and on 197 HCC case-control pairs in the SCHS. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for HCC with elevated levels of cytokines with adjustment for body mass index, alcohol drinking, cigarette smoking, seropositivity of hepatitis surface antigen (HBsAg), and history of diabetes.
Results: sCD137 levels were statistically significantly higher in HCC cases than controls in both cohorts. Compared with the 1st quartile (Q1) of sCD137, multivariable-adjusted ORs (95% CI) of HCC for the 4th quartile (Q4) were 3.8 (1.7-8.3) in the SCS and 3.5 (1.4 -8.5) in the SCHS (both Ptrend’s &lt; 0.001). Among HBsAg-negative individuals, ORs (95% CIs) for Q2, Q3, & Q4 of sCD137 were 2.7 (1.5-4.9), 2.7 (1.4-5.0), and 4.5 (2.4-8.5), respectively, compared with Q1 (Ptrend &lt; 0.001) in both SCS and SCHS combined. The corresponding ORs (95% CIs) among HBsAg- positive individuals were 21.0 (9.3-47.6), 34.1 (13.8-84.2), and 56.7 (23.3-137.9), respectively, with a P=0.095 for multiplicative interaction. The sCD137-HCC risk association remained constant over different time periods from blood draw to HCC diagnosis: ORs (95% CIs) for Q4 vs. Q1 were 4.7 (1.2-17.5) for &lt;5 years, 3.7 (1.3-10.6) for 5-10 years, and 3.94 (1.6-9.5) for more than 10 years between blood collection and cancer diagnosis. sFas was positively associated with HCC risk in the SCHS but not in the SCS. There was no statistically significant association for perforin, MIP-1β, or TNF-α with HCC risk in either cohort.
Conclusion: These novel and validated findings demonstrated that serum sCD137 levels were significantly elevated many years prior to HCC diagnosis, and had a potential synergistic effect with chronic viral infection on the HCC risk. sCD137 may be developed as a immune monitoring biomarker for risk stratification and assessment, which can lead to early diagnosis and improve prognosis of HCC patients.
Citation Format: Claire E. Thomas, Jennifer J. Adibi, Allison L. Kuipers, Brenda Diergaarde, Hung N. Luu, Aizhen Jin, Woon-Puay Koh, Yu-Tang Gao, Jennifer Adams-Haduch, Renwei Wang, Anna Lokshin, Jaideep Behari, Jian-Min Yuan. Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3015.