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

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.

Comprehensive analysis of prognostic gene signatures based on immune infiltration of ovarian cancer

“…Also, IFN plays a crucial role in tumor immunity. On the one hand, IFN exerts an anti-tumour effect, suppresses tumour proliferation, and perform immune elimination by activating cytotoxic lymphocytes (CTLs), dendritic cells (DCS) and other immune cells [ 88 ]; On the other hand, IFN-γ upregulates PD-L1 and cause programmed death of immune cells, which enables tumour cells to escape the destructive effect of the immune system, resulting in anti-tumour treatment tolerance [ 89 ]. Therefore, it is necessary to ensure that patients can benefit from immunotherapy while assuring the stable antitumor effect of IFN.…”

Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients

“…Yet another report showed that free oxaliplatin or phase-transition nanoparticles loaded with oxaliplatin caused translocation of CRT to the surface of ID8 mouse ovarian surface epithelial cell line, which is used as a syngeneic mouse model for human ovarian cancer. Moreover, studies demonstrated that the inhibition of ROS production in ID8 cells completely blocked appearance of surface CRT, pointing at ROS requirement in oxaliplatin-mediated chaperone expression [ 111 ].…”

Potential Therapeutic and Prognostic Values of LSM Family Genes in Breast Cancer

“…However, in nearly one-third of patients, cancerous growth has already spread to regional lymph nodes at the time of diagnosis [67]. Therefore, it is necessary to investigate novel prognostic techniques for early-stage detection, which employ new biomarkers in a vital role [68][69][70][71][72][73]. Furthermore, characterizing the immune system, profiling the TME, and constructing BRCA immunotherapies are also known as critical keys in cancer research [74,75].…”