TY - JOUR
T1 - Oncolytic virus-derived type I interferon restricts CAR T cell therapy
AU - Evgin, Laura
AU - Huff, Amanda L.
AU - Wongthida, Phonphimon
AU - Thompson, Jill
AU - Kottke, Tim
AU - Tonne, Jason
AU - Schuelke, Matthew
AU - Ayasoufi, Katayoun
AU - Driscoll, Christopher B.
AU - Shim, Kevin G.
AU - Reynolds, Pierce
AU - Monie, Dileep D.
AU - Johnson, Aaron J.
AU - Coffey, Matt
AU - Young, Sarah L.
AU - Archer, Gary
AU - Sampson, John
AU - Pulido, Jose
AU - Perez, Luis Sanchez
AU - Vile, Richard
N1 - Funding Information:
The authors thank Steven A. Rosenberg, Richard A. Morgan, and Steven Feldman of the Surgery Branch at the National Cancer Institute for providing us with the EGFRvIII CAR retroviral construct. The authors thank Toni L. Woltman for expert secretarial assistance. This work was funded in part by Fraternal Order of Eagles Cancer Research Fund, Fellowship Program (to L. Evgin), The European Research Council (to R.G. Vile), The Richard M. Schulze Family Foundation (to R.G. Vile), the Mayo Foundation (to R.G. Vile), the NIH (R01CA175386, R01CA108961, P50 CA210964 to R.G. Vile), a grant from Terry and Judith Paul (to J.S. Pulido), and a research grant from Oncolytics Biotech Inc (to R.G. Vile). The salary of A. Huff and C. Driscoll was supported in part by grant T32 AI132165 from the National Institutes of Health.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-17011-z
DO - 10.1038/s41467-020-17011-z
M3 - Article
C2 - 32581235
AN - SCOPUS:85086894678
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3187
ER -