The correlation of BER protein, IRF3 with CD8+ T cell and their prognostic significance in upper tract urothelial carcinoma

Abstract

Lin-ang Wang,1,* Bo Yang,2,* Wen Rao,2 Hualiang Xiao,3 Dong Wang,2 Jun Jiang1 1Department of Urology, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University), Chongqing 400042, People’s Republic of China; 2Cancer Center, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University), Chongqing 400042, People’s Republic of China; 3Department of Pathology, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University), Chongqing 400042, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun JiangDepartment of Urology, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University), Chongqing 400042, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: Tumor-infiltrating lymphocytes (TILs) play a crucial role in anti-tumor immunity. Basic studies have found that stimulator of interferon genes (STING), activated by sensing DNA damage, plays a role in recruiting and activating TILs in tumors. However, the correlation between base excision repair (BER) pathway, STING pathway and TILS and their effect on prognosis in upper urinary tract urothelial carcinoma (UTUC) are still unclear. The aim of this study was to investigate the prognostic effect of those proteins expression for disease-free survival (DFS) and overall survival (OS) and explore the correlation between these makers.Methods: We evaluated immunohistochemical expression of BER pathway (APE1, NTH1, OGG1, XRCC1, polβ), STING pathway (STING, IRF3), TILs (CD4, CD8, CD20) and PD-L1, PD-L2 in 88 UTUC patients to determine the predictive significance in DFS, OS and the correlation between them.Results: We found that interferon regulatory factor3 (IRF3) (HR: 0.451, 95% CI 0.243–0.837, p=0.024) and CD8 (HR: 0.522, 95% CI 0.295–0.926, p=0.014) are independent prognostic factors for DFS, APE1 (HR: 1.932, 95% CI 1.005–3.714, P=0.048), polβ (HR: 2.620, 95% CI 1.373–5.000, P=0.003), CD8 (HR: 0.323, 95% CI 0.151–0.693, P=0.004) were independent prognostic factors for OS. A model consisting of stage, grade, lymphovascular invasion and expression of APE1, polβ, IRF3, CD4, CD8 that predicts 3-year OS. Furthermore, DNA damage repair protein polβ is associated with CD8+ T cells in TME.Conclusion: We found that DNA damage, IRF3 and TILs are independent predictors for prognosis. We also provided clinical evidence that DNA damage repair-activated STING pathway can induce the recruitment and activation of TILs, which is consistent with preclinical models.Keywords: BER, IRF3, tumor-infiltrating lymphocytes, prognosis

Keywords

• BER
• IRF3
• tumor-infiltrating lymphocytes
• prognosis