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Theranostics 2018; 8(12):3198-3213. doi:10.7150/thno.24699 This issue Cite

Research Paper

DNA damage predicts prognosis and treatment response in colorectal liver metastases superior to immunogenic cell death and T cells

Johannes Laengle^1,6, Judith Stift², Agnes Bilecz³, Brigitte Wolf¹, Andrea Beer², Balazs Hegedus^1,3, Stefan Stremitzer¹, Patrick Starlinger¹, Dietmar Tamandl⁴, Dietmar Pils^1,5✉, Michael Bergmann^1,6✉

1. Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
2. Department of Pathology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Waehringer Guertel 18-20, A‑1090 Vienna, Austria
3. 2nd Department of Pathology, Semmelweis University, Üllői út 93, H-1091 Budapest, Hungary
4. Division of Cardiovascular and Interventional Radiology, Department of Biomedical Imaging and Image-guided Therapy, Comprehensive Cancer Center Vienna, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
5. Institute of Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Spitalgasse 23, A‑1090 Vienna, Austria
6. Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria

✉ Corresponding authors: Dietmar Pils; Email: dietmar.pilsac.at; Phone: +43 1 40400 22070; Fax: +43 1 40400 66740; Michael Bergmann; Email: michael.bergmannac.at; Phone: +43 1 40400 73744; Fax: +43 1 40400 73593

Abstract

Preclinical models indicate that DNA damage induces type I interferon (IFN), which is crucial for the induction of an anti-tumor immune response. In human cancers, however, the association between DNA damage and an immunogenic cell death (ICD), including the release and sensing of danger signals, the subsequent ER stress response and a functional IFN system, is less clear.

Methods: Neoadjuvant-treated colorectal liver metastases (CLM) patients, undergoing liver resection in with a curative intent, were retrospectively enrolled in this study (n=33). DNA damage (γH2AX), RNA and DNA sensors (RIG-I, DDX41, cGAS, STING), ER stress response (p-PKR, p-eIF2α, CALR), type I and type II IFN- induced proteins (MxA, GBP1), mature dendritic cells (CD208), and cytotoxic and memory T cells (CD3, CD8, CD45RO) were investigated by an immunohistochemistry whole-slide tissue scanning approach and further correlated with recurrence-free survival (RFS), overall survival (OS), radiographic and pathologic therapy response.

Results: γH2AX is a negative prognostic marker for RFS (HR 1.32, 95% CI 1.04-1.69, p=0.023) and OS (HR 1.61, 95% CI 1.23-2.11, p<0.001). A model comprising of DDX41, STING and p-PKR predicts radiographic therapy response (AUC=0.785, p=0.002). γH2AX predicts prognosis superior to the prognostic value of CD8. CALR positively correlates with GBP1, CD8 and cGAS. A model consisting of γH2AX, p-eIF2α, DDX41, cGAS, CD208 and CD45RO predicts pathological therapy response (AUC=0.944, p<0.001).

Conclusion: In contrast to preclinical models, DNA damage inversely correlated with ICD and its associated T cell infiltrate and potentially serves as a therapeutic target in CLM.

Keywords: DNA damage, calreticulin, immunogenic cell death, colorectal liver metastases

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