Original Article

Cancer Immunology, Immunotherapy

, Volume 62, Issue 11, pp 1675-1685

Decreased expression of interleukin-36α correlates with poor prognosis in hepatocellular carcinoma

  • Qiu-Zhong PanAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
  • , Ke PanAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
  • , Jing-Jing ZhaoAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
  • , Ju-Gao ChenAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
  • , Jian-Jun LiAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
  • , Lin LvAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
  • , Dan-Dan WangAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
  • , Hai-Xia ZhengAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
  • , Shan-Shan JiangAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
    • , Xiao-Fei ZhangAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center
    • , Jian-Chuan XiaAffiliated withState Key Laboratory of Oncology in South China, Department of Biotherapy, Sun Yat-Sen University Cancer Center Email author 

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Abstract

Interleukin-36α (IL-36α) has been found to have a prominent role in the pathogenesis of inflammatory disorders; however, little is known about the role of IL-36α in cancer. In this study, we investigated the expression, prognostic value, and the underlying antitumor mechanism of IL-36α in hepatocellular carcinoma (HCC). From immunohistochemistry analysis, IL-36α expression was lower in poorly differentiated HCC cells. In clinicopathological analysis, low IL-36α expression significantly correlated with tumor size, histological differentiation, tumor stage, and vascular invasion, and low intratumoral IL-36α expression had significantly worse overall survival rates and shorter disease-free survival rates. Moreover, intratumoral IL-36α expression was an independent risk factor for overall survival. Consecutive sections were used to detect CD3+, CD8+, and CD4+ tumor-infiltrating lymphocytes (TILs), and we found that high-IL-36α-expressing tumor tissues exhibited a significantly higher proportion of intratumoral CD3+ and CD8+ TILs, but not CD4+ TILs. Our in vitro model confirmed that supernatant from IL-36α-overexpressing human HCC cells had an increased capacity to recruit CD3+ and CD8+ T cells. Consistently, mouse HCC cells engineered to overexpress IL-36α demonstrated markedly delayed growth in vivo, as well as higher levels of intratumoral CD3+ and CD8+ TILs, compared with control mice. In vitro chemotaxis analysis also showed that mouse HCC cells overexpressing IL-36α could recruit more number of CD3+ and CD8+ T cells. These results show that IL-36α expression may play a pivotal role in determining the prognosis of patients with HCC, which we attribute to the activation of adaptive T cell immunity, especially CD8+ T cell immune response.

Keywords

Hepatocellular carcinoma Interleukin-36α Prognosis Tumor-infiltrating lymphocytes