Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity
| Autor: | Donald Bastin, John C. Bell, Charles Lefebvre, Jonathan L. Bramson, Lan Chen, Yonghong Wan, David F. Stojdl, Andrew Nguyen, Christopher J. Storbeck, Scott R. Walsh |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment T-Lymphocytes Melanoma Experimental Cell therapy 03 medical and health sciences Mice Antigen Cancer immunotherapy Cell Line Tumor medicine Animals Mice Knockout Oncolytic Virotherapy Tumor microenvironment business.industry Melanoma Interferon-alpha General Medicine Immunotherapy Interferon-beta medicine.disease Adoptive Transfer 3. Good health Blockade Oncolytic virus 030104 developmental biology Cancer research business Research Article Signal Transduction |
| Popis: | Despite its success in treating melanoma and hematological malignancies, adoptive cell therapy (ACT) has had only limited effects in solid tumors. This is due in part to a lack of specific antigen targets, poor trafficking and infiltration, and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVVs) to drive expansion and tumor infiltration of transferred antigen-specific T cells and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequences when the antigen targeted was a self-protein. However, modulation of IFN-α/-β signaling, either by functional blockade or rational selection of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN-α/-β in facilitating autoimmune toxicity during cancer immunotherapy and presents a safe and powerful combinatorial regimen with immediate translational applications. |
| Databáze: | OpenAIRE |
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