Expanding cross-presenting dendritic cells enhances oncolytic virotherapy and is critical for long-term anti-tumor immunity

Judit Svensson-Arvelund (), Sara Cuadrado-Castano, Gvantsa Pantsulaia, Kristy Kim, Mark Aleynick, Linda Hammerich, Ranjan Upadhyay, Michael Yellin, Henry Marsh, Daniel Oreper, Suchit Jhunjhunwala, Christine Moussion, Miriam Merad, Brian D. Brown, Adolfo García-Sastre and Joshua D. Brody ()
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Judit Svensson-Arvelund: Icahn School of Medicine at Mount Sinai
Sara Cuadrado-Castano: Icahn School of Medicine at Mount Sinai
Gvantsa Pantsulaia: Icahn School of Medicine at Mount Sinai
Kristy Kim: Icahn School of Medicine at Mount Sinai
Mark Aleynick: Icahn School of Medicine at Mount Sinai
Linda Hammerich: Icahn School of Medicine at Mount Sinai
Ranjan Upadhyay: Icahn School of Medicine at Mount Sinai
Michael Yellin: Celldex Therapeutics, Inc
Henry Marsh: Celldex Therapeutics, Inc
Daniel Oreper: Genentech
Suchit Jhunjhunwala: Genentech
Christine Moussion: Genentech
Miriam Merad: Icahn School of Medicine at Mount Sinai
Brian D. Brown: Icahn School of Medicine at Mount Sinai
Adolfo García-Sastre: Icahn School of Medicine at Mount Sinai
Joshua D. Brody: Icahn School of Medicine at Mount Sinai

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Immunotherapies directly enhancing anti-tumor CD8+ T cell responses have yielded measurable but limited success, highlighting the need for alternatives. Anti-tumor T cell responses critically depend on antigen presenting dendritic cells (DC), and enhancing mobilization, antigen loading and activation of these cells represent an attractive possibility to potentiate T cell based therapies. Here we show that expansion of DCs by Flt3L administration impacts in situ vaccination with oncolytic Newcastle Disease Virus (NDV). Mechanistically, NDV activates DCs and sensitizes them to dying tumor cells through upregulation of dead-cell receptors and synergizes with Flt3L to promote anti-tumor CD8+ T cell cross-priming. In vivo, Flt3L-NDV in situ vaccination induces parallel amplification of virus- and tumor-specific T cells, including CD8+ T cells reactive to newly-described neoepitopes, promoting long-term tumor control. Cross-presenting conventional Type 1 DCs are indispensable for the anti-tumor, but not anti-viral, T cell response, and type I IFN-dependent CD4+ Th1 effector cells contribute to optimal anti-tumor immunity. These data demonstrate that mobilizing DCs to increase tumor antigen cross-presentation improves oncolytic virotherapy and that neoepitope-specific T cells can be induced without individualized, ex vivo manufactured vaccines.

Date: 2022
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DOI: 10.1038/s41467-022-34791-8

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