Nat Immunol. 2020 Nov 2. doi: 10.1038/s41590-020-00810-3. | PubMed

Faezzah Baharom¹, Ramiro A Ramirez-Valdez¹, Kennedy K S Tobin¹, Hidehiro Yamane¹, Charles-Antoine Dutertre^2,3,4, Ahad Khalilnezhad^2,5, Glennys V Reynoso⁶, Vincent L Coble⁷, Geoffrey M Lynn⁷, Matthew P Mulè^8,9, Andrew J Martins⁸, John P Finnigan¹⁰, Xiao Meng Zhang², Jessica A Hamerman¹¹, Nina Bhardwaj¹⁰, John S Tsang⁸, Heather D Hickman⁶, Florent Ginhoux^2,4,12, Andrew S Ishizuka^1,7, Robert A Seder¹³

1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
2. Singapore Immunology Network, A*STAR, Singapore, Singapore.
3. Program in Emerging Infectious Disease, Duke-National University of Singapore Medical School, Singapore, Singapore.
4. Singhealth Translational Immunology and Inflammation Centre, Singapore, Singapore.
5. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
6. Viral Immunity and Pathogenesis Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
7. Avidea Technologies, Baltimore, MD, USA.
8. Systems Genomics and Bioinformatics Unit, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
9. Department of Medicine, University of Cambridge, Cambridge, UK.
10. Department of Medicine, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
11. Immunology Program, Benaroya Research Institute, Seattle, WA, USA.
12. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai, China.
13. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. rseder@nih.gov.

Abstract

Personalized cancer vaccines are a promising approach for inducing T cell immunity to tumor neoantigens. Using a self-assembling nanoparticle vaccine that links neoantigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we show how the route and dose alter the magnitude and quality of neoantigen-specific CD8+ T cells. Intravenous vaccination (SNP-IV) induced a higher proportion of TCF1+PD-1+CD8+ T cells as compared to subcutaneous immunization (SNP-SC). Single-cell RNA sequencing showed that SNP-IV induced stem-like genes (Tcf7, Slamf6, Xcl1) whereas SNP-SC enriched for effector genes (Gzmb, Klrg1, Cx3cr1). Stem-like cells generated by SNP-IV proliferated and differentiated into effector cells upon checkpoint blockade, leading to superior antitumor response as compared to SNP-SC in a therapeutic model. The duration of antigen presentation by dendritic cells controlled the magnitude and quality of CD8+ T cells. These data demonstrate how to optimize antitumor immunity by modulating vaccine parameters for specific generation of effector or stem-like CD8+ T cells.

Presented By Faezzah Baharom | ORCID iD