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

Interleukin-36 alpha (IL-36 alpha) has been found to have a prominent role in the pathogenesis of inflammatory disorders; however, little is known about the role of IL-36 alpha in cancer. In this study, we investigated the expression, prognostic value, and the underlying antitumor mechanism of IL-36 alpha in hepatocellular carcinoma (HCC). From immunohistochemistry analysis, IL-36 alpha expression was lower in poorly differentiated HCC cells. In clinicopathological analysis, low IL-36 alpha expression significantly correlated with tumor size, histological differentiation, tumor stage, and vascular invasion, and low intratumoral IL-36 alpha expression had significantly worse overall survival rates and shorter disease-free survival rates. Moreover, intratumoral IL-36 alpha 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-36 alpha-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-36 alpha-overexpressing human HCC cells had an increased capacity to recruit CD3(+) and CD8(+) T cells. Consistently, mouse HCC cells engineered to overexpress IL-36 alpha 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-36 alpha could recruit more number of CD3(+) and CD8(+) T cells. These results show that IL-36 alpha 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.