Svensson-Arvelund et al. demonstrated that vaccination with oncolytic Newcastle Disease Virus (NDV) induced tumor antigen uptake and DC activation that synergized with Flt3L to promote antitumor CD8+ T cell cross-priming and long-term tumor control. Flt3L-NDV in situ vaccination improved T cell cross-priming, amplified virus- and tumor-specific T cells, including neoepitope-reactive CD8+ T cells, and promoted durable tumor regressions. Cross-presenting cDC1s were indispensable for a functional antitumor CD8+ T cell response, whereas type I IFNs and CD4+ T cells played complementary roles in promoting optimal antitumor immunity.
Contributed by Shishir Pant
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.
Author Info: (1) Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. judit.arvelund@liu.se. Division of Molecular Medicine and Virology, Departme
Author Info: (1) Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. judit.arvelund@liu.se. Division of Molecular Medicine and Virology, Department of Clinical and Experimental Medicine, Linkping University, Linkping, 582 25, Sweden. judit.arvelund@liu.se. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. judit.arvelund@liu.se. (2) Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (3) Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (4) Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (5) Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (6) Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Department of Hepatology and Gastroenterology, Campus Virchow- Klinikum, Charit Universittsmedizin Berlin, Berlin, 13353, Germany. (7) Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (8) Celldex Therapeutics, Inc, Needham, MA, 02494, USA. (9) Celldex Therapeutics, Inc, Needham, MA, 02494, USA. (10) Genentech, South San Francisco, CA, 94080, USA. (11) Genentech, South San Francisco, CA, 94080, USA. (12) Genentech, South San Francisco, CA, 94080, USA. (13) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (14) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (15) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (16) Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. joshua.brody@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. joshua.brody@mssm.edu. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. joshua.brody@mssm.edu.
