Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells

Faezzah Baharom, Ramiro A. Ramirez-Valdez, Kennedy K.S. Tobin, Hidehiro Yamane, Charles Antoine Dutertre, Ahad Khalilnezhad, Glennys V. Reynoso, Vincent L. Coble, Geoffrey M. Lynn, Matthew P. Mulè, Andrew J. Martins, John P. Finnigan, Xiao Meng Zhang, Jessica A. Hamerman, Nina Bhardwaj, John S. Tsang, Heather D. Hickman, Florent Ginhoux, Andrew S. Ishizuka, Robert A. Seder

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

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.

Original languageEnglish
Pages (from-to)41-52
Number of pages12
JournalNature Immunology
Volume22
Issue number1
DOIs
StatePublished - Jan 2021

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