Dataset Information

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

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.

SUBMITTER: Baharom F

PROVIDER: S-EPMC7746638 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Baharom Faezzah F Ramirez-Valdez Ramiro A RA Tobin Kennedy K S KKS Yamane Hidehiro H Dutertre Charles-Antoine CA Khalilnezhad Ahad A Reynoso Glennys V GV Coble Vincent L VL Lynn Geoffrey M GM Mulè Matthew P MP Martins Andrew J AJ Finnigan John P JP Zhang Xiao Meng XM Hamerman Jessica A JA Bhardwaj Nina N Tsang John S JS Hickman Heather D HD Ginhoux Florent F Ishizuka Andrew S AS Seder Robert A RA

Nature immunology 20201102 1

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 ...[more]

PMID: 33139915

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Project description:BackgroundImmune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however, only a subset of patients with certain types of cancer achieve durable remission. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term tumor immune reprogramming and arrest cancer progression. We developed a clinically relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumor-specific CD8 T cells (TST) differentiated in mice with early sporadic lesions as compared with late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, impact TST function and liver cancer progression.MethodsMice with a germline floxed allele of the SV40 large T antigen (TAG) undergo spontaneous recombination and activation of the TAG oncogene, leading to rare early cancerous TAG-expressing lesions that inevitably progress to established liver cancer. We assessed the immunophenotype (CD44, PD1, TCF1, and TOX expression) and function (TNFα and IFNγ cytokine production) of tumor/TAG-specific CD8 T cells in mice with early and late liver lesions by flow cytometry. We vaccinated mice, either alone or in combination with ICB, to test whether these immunotherapeutic interventions could stop liver cancer progression and improve survival.ResultsIn mice with early lesions, a subset of TST were PD1+ TCF1+ TOX- and could produce IFNγ while TST present in mice with late liver cancers were PD1+ TCF1lo/- TOX+ and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitope-expressing Listeria monocytogenes (LMTAG) blocked liver cancer development and led to a population of TST that were PD1-heterogeneous, TCF1+ TOX- and polyfunctional cytokine producers. Vaccine-elicited TCF1+TST could self-renew and differentiate, establishing them as progenitor TST. In contrast, ICB administration did not slow cancer progression or improve LMTAG vaccine efficacy.ConclusionVaccination, but not ICB, generated a population of functional progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. In patients with early cancers or at high risk of cancer recurrence, immunization may be the most effective strategy.

Dataset Information

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

Publications

Intravenous nanoparticle vaccination generates stem-like TCF1<sup>+</sup> neoantigen-specific CD8<sup>+</sup> T cells.

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