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Oncolytic virus-derived type I interferon restricts CAR T cell therapy
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Journal Article
Oncolytic virus-derived type I interferon restricts CAR T cell therapy
2020
Overview
The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNβ infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNβ. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.
Oncolytic viruses promote an inflammatory response and elicit anti-tumor immunity. Here the authors show, unexpectedly, that the oncolytic virus, VSVIFNβ, induces type I interferon responses that, when combined with chimeric antigen receptor (CAR) T therapy, lead to the attrition of both CAR T and conventional T cells, thus dampening their anti-tumor activity.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/21
/ 13/31
/ 13/44
/ 42
/ 42/44
/ 42/70
/ 64
/ 64/60
/ Animals
/ Antigens
/ Female
/ Humanities and Social Sciences
/ Interferon-beta - metabolism
/ Melanoma, Experimental - immunology
/ Melanoma, Experimental - therapy
/ Mice
/ Oncolytic Viruses - genetics
/ Oncolytic Viruses - metabolism
/ Receptor, Interferon alpha-beta - genetics
/ Receptor, Interferon alpha-beta - metabolism
/ Receptors, Antigen, T-Cell - metabolism
/ Receptors, Chimeric Antigen - metabolism
/ Science
/ Therapy
/ Tumors
/ Viruses
