Abstract
Depending on the initiating stimulus, cancer cell death can be immunogenic or non-immunogenic. Inducers of immunogenic cell death (ICD) rely on endoplasmic reticulum (ER) stress for the trafficking of danger signals such as calreticulin (CRT) and ATP. We found that nanosecond pulsed electric fields (nsPEF), an emerging new modality for tumor ablation, cause the activation of the ER-resident stress sensor PERK in both CT-26 colon carcinoma and EL-4 lymphoma cells. PERK activation correlates with sustained CRT exposure on the cell plasma membrane and apoptosis induction in both nsPEF-treated cell lines. Our results show that, in CT-26 cells, the activity of caspase-3/7 was increased fourteen-fold as compared with four-fold in EL-4 cells. Moreover, while nsPEF treatments induced the release of the ICD hallmark HMGB1 in both cell lines, extracellular ATP was detected only in CT-26. Finally, in vaccination assays, CT-26 cells treated with nsPEF or doxorubicin equally impaired the growth of tumors at challenge sites eliciting a protective anticancer immune response in 78% and 80% of the animals, respectively. As compared to CT-26, both nsPEF- and mitoxantrone-treated EL-4 cells had a less pronounced effect and protected 50% and 20% of the animals, respectively. These results support our conclusion that nsPEF induce ER stress, accompanied by bona fide ICD.
Highlights
Several local ablative therapies are available as innovative treatments to fight cancer
We investigated the efficacy of nanosecond pulsed electric fields (nsPEF) treatment at inducing endoplasmic reticulum (ER) stress and immunogenic cell death (ICD) in both immunogenic CT-26 colon carcinoma and poorly immunogenic EL-4 lymphoma cells
We previously reported that nsPEF induce apoptosis in U-937 monocyte lymphoma but not in B16F10 melanoma cells
Summary
Several local ablative therapies are available as innovative treatments to fight cancer. Ablative therapies make tumor antigens available as an in situ cancer vaccine which has the potential to initiate a systemic antitumor immune response. Thermal ablation technologies such as radiofrequency ablation (RFA), microwave ablation (MWA), and high intensity focused ultrasound (HIFU) have all been shown to elicit immunomodulatory effects, the magnitude of which is highly variable [1]. The potential of dead and dying cells to trigger an antitumor immune response depends on the regulated emission of DAMPs, such as the endoplasmic reticulum protein calreticulin (CRT), ATP, and the chromatin-binding protein high mobility group B1 (HMGB1) These signals are crucial for immunogenic cell death (ICD). NsPEF-treated CT26 and EL-4 tumor cells vaccinated 78% and 50% of the animals from tumor challenge, respectively
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