Abstract 1086: ZFP36L2 is expected to be a potential prognostic marker in IL-1β+ osteosarcoma patients
Authors: Hao Peiyao , Luo Piaopiao , Ren Zhenhua , Xu Shenglin , Han Jijun , Nan Xiang 
Published: March 2024

Background: Osteosarcoma (OS) is the most common bone malignancy affect children and young adults. For decades, the long-term survival for patients with recurrences and metastases remains ~30%. There’s an urgent need for new prognostic marker and therapeutic options. ZFP36L2, a member of the tristetraprolin (TTP) family of CCCH zinc finger proteins, stands out for its pivotal role in post transcriptional modifications and modify tumor microenvironment (TME). Notably, ZFP36L2 contributes to the recruitment of macrophages, specifically the M1 subtype, which are known for their ability to secrete IL1β and exhibit anti-tumor functions. Our study reveals that, ZFP36L2 can be used as a predictor of prognosis in OS patients with enriched IL1B expression. This study aims to elucidate the interaction between ZFP36L2 and IL1B in modification of TME and shed light on its potential of prognosis prediction and therapeutic in IL1β positive OS patients.

Methods: Firstly, we conducted a comprehensive exploration of ZFP36L2 expression across TCGA cohorts. Then, we performed IHC staining to confirm the evaluated expression of ZFP36L2 in cancerous tissues. Immune infiltration analysis, including QUANTISEQ, TIMER, and CIBERSORT, was conducted. KM plot was employed to analyze the prognosis of OS patients. Finally, qPCR and western blot were used to validate transcriptional and translational changes of key molecules across OS cell lines.

Results: Our findings demonstrate that ZFP36L2 exhibits specific expression across various cancer types, with a notable elevation in sarcoma tissues, as confirmed by IHC. Importantly, this high expression of ZFP36L2 in sarcoma tissues is correlated with metastasis. We found ZFP36L2 significantly correlates with tumor metastasis but failed in patient overall survival. Immunoinfiltration analysis indicates a significant correlation between ZFP36L2 and macrophages, as well as T cells, suggesting a role in the TME. Prognostic analysis reveals that ZFP36L2 can serve as a predictive marker for IL1β positive patients. The wetlab experiments demonstrated that ZFP36L2 leads to IRGM mRNA degradation, ultimately affecting IL1β+ macrophages.

Conclusion: This study delineates the tumor-specific elevated expression of ZFP36L2 and its potential as a prognostic marker in IL1β+ OS patients. We hypothesize that ZFP36L2 affects IL1β+ macrophages through IRGM degradation. Besides, IRGM also has an impact on cytotoxic T cells. Therefore, the ZFP36L2-IRGM axis plays an important role in remodeling OS TME. These results indicated ZFP36L2, not only serves as a marker, but also can be a therapeutic target in IL1β enriched patients.

Citation Format: Peiyao Hao, Piaopiao Luo, Zhenhua Ren, Shenglin Xu, Jijun Han, Xiang Nan. ZFP36L2 is expected to be a potential prognostic marker in IL-1β+ osteosarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1086.