Abstract 6119: The Correlation analysis of driver genes of JAK-STAT signaling pathway with tumor immune microenvironment and prognosis in hepatocellular carcinoma
Authors: Yang Dinghua , Yu Sheng , Guo Baitang , Chen Tingting 
Published: June 2022

Background: The JAK/STAT pathway, which transmits signals that are crucial for growth, differentiation, immunity and survival, is altered in pan-cancer. And the downstream transcription factor STAT3 acts on the PD-L1 promoter and induced PD-L1 upregulation of in tumor. The roles of JAK-STAT signaling pathway in hepatocellular carcinoma (HCC), and its correlation with tumor immune microenvironment (TIME) and prognosis remain unclear.

Method: 34 patients with HCC who underwent radical surgical resection at Southern Medical University Nanfang hospital were enrolled. Tumor tissue samples were collected for next generation sequencing (NGS) testing (733 genes panel) and multiple immunohistochemical fluorescence staining (mIHC). Clinical information was obtained to evaluate the prognostic performance of biomarkers. Whole exome sequencing data of 366 HCC patients was obtained from the Cancer Genome Altas (TCGA), and the tumor-related immune cells infiltration level difference between mutant and wild-type tumors were inferred using TIMER2.0.

Results: Characteristics of 34 HCC patients from Nanfang cohort were as follows: 58.5% HBV positive, 41.2% largest tumor diameter≥5cm, 73.5% liver cirrhosis, 20.6% AFP &gt; 400ng/ml, 67.6% MVI, 11.8% PVTT, 73.5% BCLC A, 85.3% CNLC I/II. 44% (15/34) HCC patients harboring JAK-STAT pathway related gene mutation, which EP300, STAT3 and JAK1 were the top three alternation frequency genes. The JAK-STAT pathway mutant tumors with significantly higher inferred M2 macrophages than wild-type (mean density, mutation vs. wild-type = 2.755 vs. 1.407 cells/mm2, p= 0.036). The level of infiltration of PD-L1 expression macrophages was significantly increased in the JAK - STAT pathway mutated tumors compared with wild-type tumors (p =0.048). After median follow-up time was 5.4 months, 3 short-term recurrence events were recorded. The recurrence-free survival (RFS) of EP300 and/or STAT3 mutation group (n=5) were longer than wild-type group (n=29) (median RFS, mutation vs. wild-type = 5.6 vs. NE months; HR 7.267[95% CI 0.46-113.8]; P = 0.057). While in TCGA cohort, the level of infiltration of M2 macrophages was increased in both STAT3 and EP300 mutant tumors compared with wild-type tumors (Wilcoxon test, p &lt; 0.05). The significance of STAT3 and EP300 expression in cancer cells were evaluated on samples stratified by tumor-infiltrating macrophages M2 cells, which were divided into 4 groups respectively. Both RFS of high gene expression and high macrophages M2 groups were significantly different among the four groups (log-rank P&lt;0.05).

Conclusion: STAT3 and EP300 are driver genes of JAK-STAT signaling pathway in HCC. The JAK-STAT pathway mutation was associated with M2 macrophage infiltration and increased PD-L1 expression of macrophages, suggesting a poor prognosis.

Citation Format: Dinghua Yang, Sheng Yu, Baitang Guo, Tingting Chen. The Correlation analysis of driver genes of JAK-STAT signaling pathway with tumor immune microenvironment and prognosis in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6119.