K. Chida1,2, M. Oshi1,3, N. An4, A. M. Roy5, G. K. Mann1, L. Yan4, I. Endo3, K. Hakamada2, K. Takabe1,3,6 1Roswell Park Comprehensive Cancer Center, Department Of Surgical Oncology, Buffalo, NY, USA 2Hirosaki University Graduate School of Medicine, Department Of Gastroenterological Surgery, Hirosaki, AOMORI, Japan 3Yokohama City University Graduate School of Medicine, Department Of Gastroenterological Surgery, Yokohama, KANAGAWA, Japan 4Roswell Park Comprehensive Cancer Center, Department Of Biostatistics & Bioinformatics, Buffalo, NY, USA 5Roswell Park Comprehensive Cancer Center, Department Of Hematology And Oncology, Buffalo, NY, USA 6Jacobs School of Medicine and Biomedical Sciences, Department Of Surgery, Buffalo, NY, USA
Introduction:
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. Most HCC cases arise from chronic inflammation of the liver caused by fatty liver disease, hepatitis virus infections, and toxic substances, including alcohol. On the other hand, inflammation in an existing tumor may drive cancer progression or elicit an immune response to suppress cancer. Therefore, we investigated the clinical relevance of enhanced inflammation in patients with HCC.
Methods:
A total of 655 HCC patients from The Cancer Genome Atlas (TCGA)-HCC (n=358), GSE6764 (n=75), GSE76427 (n=115) and GSE89377 (n=107) cohorts were analyzed. To quantify the inflammatory response, we utilized a scoring system based on the gene set variation analysis of the “INFLAMMATORY_RESPONSE” gene set from the Hallmark collection. This gene set consists of 200 inflammation-related genes sourced from the molecular signatures database.
Results:
We observed that the level of inflammatory response increased progressively during the stepwise carcinogenic process of HCC, starting from normal liver to cirrhosis. However, interestingly in HCC, the inflammatory response was lower compared to any other state consistently in both GSE6764 and GSE89377 cohorts (both p<0.001). This trend of increasing inflammatory response from normal liver to cirrhosis, followed by a sharp decrease in HCC, was consistently observed in immune response-related pathways such as interferon (IFN)-α and -γ response, IL6/JAK/STAT3 signaling, complement signaling, coagulation cascade, and allograft rejection, which were consistent in both GSE6764 and GSE89377 cohorts (all p<0.02). HCC with high inflammatory response was significantly associated with high infiltration of leukocytes, lymphocytes, high T-cell receptor, and B-cell receptor richness, and cytolytic activity (all p<0.001). Immune cells including CD8 cells, CD4 memory cells, macrophages, dendritic cells, regulatory T-cells, and B-cells significantly infiltrated HCC with high inflammation (all p<0.01). Surprisingly, high inflammatory response HCC was associated with lower levels of mutation rates and neoantigens and was not associated with cell proliferation. The high inflammatory response HCC exhibited not only several pro-cancerous signals, such as epithelial mesenchymal transition, KRAS signaling, hypoxia, and angiogenesis but also immune response pathways such as IFN-α and -γ response, IL6/JAK/STAT3 signaling, complement signaling, allograft rejection, and apoptosis. HCC with a high inflammatory score had better disease-free survival in TCGA (p=0.034) and overall survival (p=0.008) in GSE76427 than that with a low score.
Conclusion:
This study highlighted the clinical relevance of inflammatory response in HCC, showing its correlation with carcinogenesis process. However, higher inflammatory response attracts immune cells and immune response that is associated with better outcome in HCC.