Prognostic value of the ratio of Interleukin-2 and Interleukin-10 in patients with hepatocellular carcinoma treated with anti-PD-1 therapy
Authors: Zhong Deyuan , Liang Yuxin , Su Yuhao , Yang Qinyan , Yan Hongtao , Shi Ying , Huang xiaolun , Shang Jin 
Published: April 2024

Abstract

Background: The progression of cancer is intricately linked to systemic immunity. However, within the hepatocellular carcinoma (HCC) patients undergoing anti-PD-1 therapy, there exists a paucity of comprehensive reports concerning the prognostic implications of immunological markers within peripheral blood. The primary objective of this investigation is to meticulously identify predictors indicative of the response to anti-PD-1 therapy in HCC patients, with a specific emphasis on immunological markers within peripheral blood. The overarching goal is to ameliorate patient outcomes through the discernment of these predictive factors. Noteworthy advancements in the treatment of HCC have been achieved through the utilization of immune checkpoint inhibitors (ICIs). Nevertheless, a conspicuous deficiency persists in the current landscape-namely, the absence of a streamlined and accessible peripheral blood-based model for the anticipation of clinical outcomes and the facilitation of judicious treatment stratagems.
Methods: A total of 30 HCC patients consecutively treated with anti-PD-1 therapy in Affiliated Hospital of University of Electronic Science and Technology of China between January 2021 and January 2023 were included in the retrospective study. Patients were divided into the tumor-progressive-free (TPF) group and tumor-progressive (TP) group based on the 48-week follow-up evaluation. The correlation between the feature indicators (e.g., immunological indicators, blood parameters and free PD-1 in peripheral blood) and clinical prognosis was analyzed. In order to delve deeper into the impact of IL-2 and IL-10 on the efficacy of immunotherapy, a comprehensive analysis was conducted utilizing integrated RNA sequencing data obtained from the Gene Expression Omnibus (GEO) and Cancer Genome Atlas (TCGA) databases. Mechanistic insights into the regulatory effects of IL-2 and IL-10 on immunotherapeutic outcomes were explored through enrichment analysis and immune cell infiltration analysis.
Results: The univariate analysis results demonstrate that IL-2 (0.0045) and IL-10 (p=0.025) were initially screened as differential predictors. Further multivariate analysis identified the ratio of IL-2 and IL-10 (odds ratio (OR) 2.918, 95% confidence interval (CI), 1.191–7.15, p=0.019) as independent prognostic factors. The ratio of IL-2 and IL-10 (AUC=0.884, 95% CI: 0.766-1, p<0.001) presented better prognostic performance than other traditional prognostic indicators. To further extend the relevance between two cytokines and anti-PD-1 therapy, we explored the expression of IL-2 and IL-10 in CD8+ T cells based on publicly available data which were collected from NCBI Gene Expression Omnibus (GEO) database. The results suggested that reduction of the expression of IL-2 (p= 0.0005) and accumulation of the expression of IL-10 (<0.0001) were shown in exhausted T cells compared with effector T cell. Moreover, analysis of The Cancer Genome Atlas (TCGA) dataset reveals that IL-2 and IL-10 exhibit involvement in immune-associated gene sets, encompassing those related to cytokine signaling pathways, innate immunity, and adaptive immunity. The expression patterns of IL-2 and IL-10 are intricately linked to the infiltration of the anti-tumor immune microenvironment by distinct immune cell populations, including B cells, T cells, dendritic cells, monocytes, macrophages, and neutrophils.
Conclusion: The research findings indicate a significant correlation between a low ratio of IL-2 to IL-10 and adverse prognosis in hepatocellular carcinoma (HCC) patients. This finding is related to the status of immune cells. In the future, the clinical significance of this indicator is worthy of further validation in large cohort samples, so as to help specify more accurate individualized treatment plan and improve the prognosis of HCC patients.