Interleukin-33 Involvement in Nonsmall Cell Lung Carcinomas: An Update

Abstract

Lung carcinogenesis is a multistep process involving genetic mutations and epigenetic changes, with the acquisition of a malignant phenotype characterized by apoptosis resistance, unregulated proliferation and differentiation, invasion, and metastatic abilities. However, neoplastic development and progression seem to be aided by non-neoplastic cells; the molecules they produced can either promote the immune response or, alternatively, support tumor pathogenesis. Consequently, the relative contribution of tumor-associated inflammatory pathways to cancer development has become crucial information. Interleukin-33 (IL-33) is an IL-1-like alarmin, and it is a ligand for the suppressor of tumorigenicity 2 (ST2) receptor. IL-33 functions as a dual role cytokine with the ability to induce T-helper-type 2 (Th2) immune cells and translocate into the nucleus, suppressing gene transcription. Although its function in immunity- and immune-related disorders is well known, its role in tumorigenesis is still debated. The IL-33/ST2 axis is emerging as a powerful modulator of the tumor microenvironment (TME) by recruiting immune cells, able to modify the TME, supporting malignant proliferation or improving antitumor immunity. In the present review, we discuss IL-33′s potential role in lung carcinogenesis and its possible application as a therapeutic target.

Development of an Immune-Related Risk Signature for Predicting Prognosis in Lung Squamous Cell Carcinoma

“…Consistent with previous evidence, interleukin-33 (IL33) and interleukin 1 receptor-like 1 (IL1RL1) were found to be increased in lung cancer and associated with disease clinical stage (Wang et al, 2016). IL-33/ST2 signaling pathway has been implicated in tumor-associated immune response and inflammatory disease of the lung (Casciaro et al, 2019), and IL-33 could significantly promote the migration and invasion of lung cancer cells through alpha serine/threonine-protein kinase (AKT) pathway activation (Yang et al, 2018). As an attractant, IL-33 can promote the recruitment of Th2-associated cytokines, which act as key mediators for the recruitment of neutrophils, monocytes, NK cells, dendritic cells or T lymphocytes in inflammatory conditions at the site of tumor (Brabcova et al, 2014).…”

IL-33 Promotes the Growth of Non-Small Cell Lung Cancer Cells Through Regulating miR-128-3p/CDIP1 Signalling Pathway

“…IL-33 inhibits NSCLC progression through various mechanisms, including diminishing regulatory T cells (Treg) cells in tumor tissues, educating immune surveillance in tumor microenvironments, abrogating polarization of M2 tumor-associated macrophages (TAMs), and reducing accumulations of Treg cells in tumor tissues. 8 , 18 These findings are mainly involved in the immune response in tumor environment. However, we speculated that the role of IL-33 on immune regulation is not dominant here.…”

The ST2/Interleukin-33 Axis in Hematologic Malignancies: The IL-33 Paradox

“…However, as far as this cytokine is concerned, we are faced with what has sometimes been defined as the IL-33 paradox. Several data have demonstrated a relevant role of IL-33 in numerous malignancies, where it may have both pro- and—less frequently—antitumorigenic actions [60,61].…”

“…Dependent on the cancer milieu, IL-33 may influence anticancer immunity, stimulating CD8-positive T cells essential for the elimination of tumor cells. Th17 and Treg cells are also immune modulators in cancer, and Th17 cells influence antitumor responses, while Treg cells have an action in the conservancy of self-tolerance and in the regulation of immune response to cancer cells [61]. Protumor action can also be exerted by the effect of the cytokine on MDSCs.…”

“…IL-33 levels were demonstrated to be a positive prognostic marker in hepatocellular carcinoma and in breast cancer cells [65,66]. IL-33, together with its receptor ST2, seems to play a key role in the tumor environment by involving different pathways, such as interferon regulatory factor-3 (IRF-3), MyD88, AKT, COT, ERK, and JNK.IL-33 may act in both a pro- and antioncogenic way by increasing cells’ metabolism and by regulating the immune system [61,67] (Table 1).…”