AIM2 Inflammasome in Tumor Cells as a Biomarker for Predicting the Treatment Response to Antiangiogenic Therapy in Epithelial Ovarian Cancer Patients

Abstract

Antiangiogenic therapy, such as bevacizumab (BEV), has improved progression-free survival (PFS) and overall survival (OS) in high-risk patients with epithelial ovarian cancer (EOC) according to several clinical trials. Clinically, no reliable molecular biomarker is available to predict the treatment response to antiangiogenic therapy. Immune-related proteins can indirectly contribute to angiogenesis by regulating stromal cells in the tumor microenvironment. This study was performed to search biomarkers for prediction of the BEV treatment response in EOC patients. We conducted a hospital-based retrospective study from March 2013 to May 2020. Tissues from 78 Taiwanese patients who were newly diagnosed with EOC and peritoneal serous papillary carcinoma (PSPC) and received BEV therapy were collected. We used immunohistochemistry (IHC) staining and analyzed the expression of these putative biomarkers (complement component 3 (C3), complement component 5 (C5), and absent in melanoma 2 (AIM2)) based on the staining area and intensity of the color reaction to predict BEV efficacy in EOC patients. The immunostaining scores of AIM2 were significantly higher in the BEV-resistant group (RG) than in the BEV-sensitive group (SG) (355.5 vs. 297.1, p < 0.001). A high level of AIM2 (mean value > 310) conferred worse PFS after treatment with BEV than a low level of AIM2 (13.58 vs. 19.36 months, adjusted hazard ratio (HR) = 4.44, 95% confidence interval (CI) = 2.01–9.80, p < 0.001). There were no significant differences in C3 (p = 0.077) or C5 (p = 0.326) regarding BEV efficacy. AIM2 inflammasome expression can be a histopathological biomarker to predict the antiangiogenic therapy benefit in EOC patients. The molecular mechanism requires further investigation.

Three-Dimensional Modelling of Ovarian Cancer: From Cell Lines to Organoids for Discovery and Personalized Medicine

“…Unlike for PARPis, there are no clinically approved biomarkers to predict responses of women with ovarian cancer to the anti-angiogenic bevacizumab, although numerous studies have focused on this area ( Buechel et al, 2021 ; Gao et al, 2021 ; Hsu et al, 2021 ). Given the advances seen in PFS and OS of some women receiving this monoclonal antibody that targets vascular endothelial growth factor (VEGF), development of functional assays to predict the likelihood that a woman will respond to bevacizumab would represent a major advance ( Burger et al, 2011 ; Perren et al, 2011 ; Oza et al, 2015 ).…”

A Weakly Supervised Deep Learning Method for Guiding Ovarian Cancer Treatment and Identifying an Effective Biomarker

“…Immunohistochemistry (IHC) with antibodies specific for EOC antigens help identify those that are overexpressed or aberrantly expressed in tumor tissues and may be a potential biomarker for therapeutic prediction. In our previous study [ 58 ], the expression of AIM2, C3 and C5 was analyzed using immunohistochemical staining according to the percentage and intensity of the color reaction by visual observation to predict the efficacy of bevacizumab in epithelial ovarian cancer (EOC) patients, and the AIM2 immunostaining scores were significantly higher in the bevacizumab-resistant group than in the bevacizumab-sensitive group ( p < 0.001), but there were no significant differences in C3 ( p = 0.077) or C5 ( p = 0.326) regarding bevacizumab. Based on the results of the previous study and this study, we propose a possible link between the AIM2 inflammasome and antiangiogenic therapy in EOC.…”

The Role of Inflammasomes in Ovarian Cancer

“…AIM2 is involved in the malignant transformation of endometriosis to clear cell and endometrioid ovarian carcinoma (64,71). This inflammasome has a high prognostic significance in several histological subtypes of ovarian cancer because overexpression of AIM2 has been reported to worsen progression-free survival of patients (70). These studies point to the significance of AIM2 as a biomarker for ovarian cancer and requires further exploration.…”

“…AIM2 drives pro-IL-18 and pro-IL-1β proteolytic cleavage without relying on NLRP3 and/or TLR (Toll-like receptor) stimuli (17,67). AIM2 is a good predictor of efficacy of antiangiogenic therapies, as observed in patients treated with bevacizumab (70). AIM2 is involved in the malignant transformation of endometriosis to clear cell and endometrioid ovarian carcinoma (64,71).…”