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 TLR7/8 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 compared to subcutaneous immunization (SNP-SC). Single cell RNA-seq 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 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.

The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

“…Of note, the method through which a therapy is administered to a patient may be a critical factor for determining the amount of TCF1 + CD8 + T cells generated in response to the therapy. As noted by Baharom et al, intravenous administration of a nanoparticle vaccine produced a significantly greater amount of stem-like TCF1 + PD-1 + CD8 + T cells in stark contrast with the administration of the vaccine via subcutaneous injection [ 94 ]. These TCF1 + PD-1 + CD8 + T cells were characterized showing a similar phenotype with stem-like T EX cell progenitors, expressing eomesodermin and CXCR3.…”

Conversations that count: Cellular interactions that drive T cell fate

“…186 A recent study has demonstrated that the route used to deliver nanoparticle vaccines dramatically alters T cell differentiation. 166 Specifically, intravenous delivery heightened differentiation toward T SCM , while subcutaneous delivery resulted in more terminally differentiated effector cells. Therefore, it appears that the route of nanoparticle entry into secondary lymphoid organs may alter where antigens are deposited.…”

“…122 The role of ASCL2 in T SCM has so far not been investigated, but, unlike CCR7 it has not been reported to be expressed in transcriptional characterization studies. 24,25,56,165,166 Despite T SCM being positioned in the lymph node paracortex or splenic T cell zone, 24 it remains unclear if these precursors require contact with B cells at the T:B border in a similar manner to that shown for T FH cells. Initial characterization of these cells demonstrated they co-expressed T FH cell-surface markers ICOS and Slamf6, both of which facilitate T FH cell engagement with B cells.…”

“…55 A recent report showed transcriptional expression of EBI2, a molecule that is similarly expressed by pre-T FH cells and directs them to the T:B border. 157,166 Again, it is unclear if in this region T SCM cells contact B cells or the IL-2 quenching dendritic cells producing the EBI2 ligand. 157 Further, when T SCM cells were transferred into B celldeficient μMT recipients they were less capable of inhibiting viral replication than those transferred into wild-type mice.…”

Development and Validation of a Unique Gignature of Cancer Stemness-related Genes for Predicting the Overall survival of Colorectal Cancer Patients

“…The interaction between the immune system and CSCs is still controversial, as the increased tumorigenicity of CSCs reveals that they can promote oncogenic immunomodulation in colon cancer [15,16]. Moreover, cancer cells and CSCs with high stemness can decrease the expression of major histocompatibility complex (MHC) molecules, thereby promoting immune evasion and decreasing the activity of anti-tumorigenic immune cells [17].…”