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

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.

IL-36 s in the colorectal cancer: is interleukin 36 good or bad for the development of colorectal cancer?

“…Additionally, IL-36α is an independent factor affecting the survival of CRC patients on multi-variate analysis. This is supported by the finding that IL-36α may exhibit anti-tumour effects in CRC progression [13], perhaps via activating adaptive T cell immune responses and recruiting CD3 + and CD8 + tumour infiltrating lymphocytes (TILs) [30].…”

Prognostic value of tumor-infiltrating lymphocytes in hepatocellular carcinoma

“…A total of 20 articles, including 3102 patients with HCC, researched the association between clinical outcome and the density of CD8+ TILs. [9,10,13,14,16,17,23,28,30,34,35,39–41,44,48,50,53–55]…”

“…Eighteen articles focused on the relationship between OS and the density of CD8+ TILs in IT. [9,10,14,16,17,23,28,30,34,35,39–41,44,50,53–55] Two articles focused on the association between OS and the density of CD8+ TILs in MT. [39,41] Five articles focused on the association between OS and the density of CD8+ TILs in PT.…”

IL36 Cooperates With Anti-CTLA-4 mAbs to Facilitate Antitumor Immune Responses

“…In addition, IL36γ stimulates Th1 differentiation in vitro and IL36R is required for protective immune responses to aspergillus and Bacillus Calmette-Guerin infection (14,25). Recent studies also show that IL36γ promotes antitumor immune responses through enhancing the effector function of type 1 lymphocytes (16,(26)(27)(28)(29)(30)(31). All these data have firmly established an important role of IL36 in promoting immune responses.…”