Sequential Interferon β-Cisplatin Treatment Enhances the Surface Exposure of Calreticulin in Cancer Cells via an Interferon Regulatory Factor 1-Dependent Manner.

Pei-Ming Yang,Yao-Yu Hsieh,Shih-Chieh Yen,Chien-Fu Hung,Jia-Ling Du

doi:10.3390/biom10040643

Abstract

Immunogenic cell death (ICD) refers to a unique form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Accumulating evidence indicates that the efficacy of conventional anticancer agents relies on not only their direct cytostatic/cytotoxic effects but also the activation of antitumor ICD. Common anticancer ICD inducers include certain chemotherapeutic agents (such as anthracyclines, oxaliplatin, and bortezomib), radiotherapy, photodynamic therapy (PDT), and oncolytic virotherapies. However, most chemotherapeutic reagents are inefficient or fail to trigger ICD. Therefore, better understanding on the molecular determinants of chemotherapy-induced ICD will help in the development of more efficient combinational anticancer strategies through converting non- or relatively weak ICD inducers into bona fide ICD inducers. In this study, we found that sequential, but not concurrent, treatment of cancer cells with interferon β (IFNβ), a type I IFN, and cisplatin (an inefficient ICD inducer) can enhance the expression of ICD biomarkers in cancer cells, including surface translocation of an endoplasmic reticulum (ER) chaperone, calreticulin (CRT), and phosphorylation of the eukaryotic translation initiation factor alpha (eIF2α). These results suggest that exogenous IFNβ may activate molecular determinants that convert cisplatin into an ICD inducer. Further bioinformatics and in vitro experimental analyses found that interferon regulatory factor 1 (IRF1) acted as an essential mediator of surface CRT exposure by sequential IFNβ-cisplatin combination. Our findings not only help to design more effective combinational anticancer therapy using IFNβ and cisplatin, but also provide a novel insight into the role of IRF1 in connecting the type I IFN responses and ICD.

Highlights

Accumulating evidence indicates that the efficacies of conventional anticancer agents rely on their direct cytostatic/cytotoxic effects and the activation of tumor-targeting immune responses [1]
We accidentally found that exogenous supplementation with interferon β (IFNβ) by the sequential treatment protocol was sufficient to enhance the ability of cisplatin to induce the expression of immunogenic cell death (ICD) biomarkers
The statistical analysis suggested that IFNβ and/or cisplatin significantly induced ecto-CRT in the cotreatment group (Figure 1B), we thought that the levels of ecto-CRT might not efficiently induce ICD based on the ecto-CRT staining (Figure 1A)

Summary

Introduction

Accumulating evidence indicates that the efficacies of conventional anticancer agents rely on their direct cytostatic/cytotoxic effects and the activation of tumor-targeting immune responses [1]. One such response is immunogenic cell death (ICD), indicating that dying cancer cells can elicit an effective antitumor immune response through the release of damage-associated molecular patterns (DAMPs). Cancer cells exposed to a lethal dose of ICD inducers in vitro and inoculated into syngeneic immunocompetent mice in the absence of adjuvants efficiently protect the animals from a subsequent challenge with living cancer cells of the same type [6]. Given that tumors are often resistant to certain death pathways, the elasticity of multimodal ICD induction may overcome the anticancer drug resistance

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Results

Conclusion