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

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.