Relationship and prognostic significance of IL-33, PD-1/PD-L1, and tertiary lymphoid structures in cervical cancer

Abstract

IL‐33, an epithelial‐derived cytokine, functions as an alarmin for the immune system in the tumor microenvironment (TME). However, the expression and role of IL‐33 on cervical cancer remain unclear. The aim of this study was to investigate the expression of IL‐33 and its relationship with clinicopathologic features, tertiary lymphoid structures (TLS), and programmed cell death 1 (PD‐1)/programmed cell death 1 ligand (PD‐L1) immune checkpoints by immunohistochemistry in 93 cervical cancer patient specimens. Down‐regulation of IL‐33 expression was observed in tumor tissues compared with adjacent tissues. More importantly, IL‐33 was detected in the cytoplasm of tumor fraction. IL‐33 expression in tumor cytoplasm was associated with tumor size and the invasive depth of tumors (p < 0.05). Meanwhile, IL‐33 expression in tumor cytoplasm was positively correlated with infiltration of CD3+ T cells, CD8+ T cells, and PD‐L1 expression in tumor tissues (p < 0.05). The number of TLS strongly correlated with the depth of tumor invasion, preoperative chemotherapy, human papillomavirus infection, and high level of PD‐1 (p < 0.05). However, there was no significant relationship between IL‐33 and TLS. Kaplan–Meier survival curves showed that the formation of TLS was associated with a better prognosis (p = 0.008). In multivariable Cox regression modeling, high expression of PD‐L1 in tumor tissues was correlated with poor prognosis (HR = 0.128; 95% CI: 0.026–0.646; p = 0.013), whereas the high expression of IL‐33 in tumor tissues was associated with better prognosis (HR = 5.097; 95% CI:1.050–24.755; p = 0.043). These results indicate that IL‐33, TLS, and PD‐L1 are potentially valuable prognostic predictor for cervical cancer. IL‐33 has potential for combination with PD‐L1‐related antitumor therapy.

Immature central tumor tertiary lymphoid structures are associated with better prognosis in non-small cell lung cancer

“…Overall, TLSs have a bivalent influence on host–tumor interactions, and they are found in almost all solid tumors. Studies have shown that TLSs indicate a favorable prognosis for most human tumors, including breast cancer [ 12 ], lung adenocarcinoma (LUAD) [ 13 ], hepatocellular carcinoma [ 14 ], colorectal cancer [ 15 ], cutaneous squamous cell carcinoma [ 16 ], gastric cancer [ 17 ], cervical cancer [ 18 ], and oral cancer [ 19 ].…”

Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions

“…IL-33 expression in the tumor cytoplasm of patients with cervical cancer is positively correlated with infiltration of CD3 + T cells, CD8 + T cells, and PD-L1 expression in tumor tissues. High IL-33 expression in tumor tissues has been associated with improved prognosis [ 247 ]. It has been reported that intracellular and extracellular IL-33 play distinct mechanistic roles; intracellular IL-33 attenuates extracellular IL-33-induced cholangiocarcinoma cell proliferation and invasion via NF-κB and GSK-3β pathways [ 48 ].…”