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Studies in a murine B16 melanoma model show that persistent antigen at vaccination sites induces CD8+ T cell sequestration, dysfunction and deletion

ABSTRACT: To understand why cancer vaccine-induced T cells often fail to eradicate tumors, we studied immune responses in mice vaccinated with gp100 peptide emulsified in incomplete Freund's adjuvant (IFA), commonly used in clinical cancer vaccine trials. After gp100 peptide/IFA vaccination, tumor-specific CD8+ T cells (adoptively transferred from gp100-specific TCR-transgenic pmel-1 mice) accumulated not in tumors but at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, IFN-γ and FasL-mediated apoptosis, resulting in systemic hyporesponsiveness to subsequent vaccination. Provision of anti-CD40 antibody, TLR7 agonist and interleukin-2 (covax) reduced T cell apoptosis but did not prevent vaccination site sequestration. A non-persisting vaccine formulation shifted T cell localization towards tumors, inducing superior anti-tumor activity. Short-lived formulation also reduced systemic T cell dysfunction and promoted memory formation, as shown by gene expression profiling and other measures. Persisting peptide/IFA vaccine depots, currently used to vaccinate cancer patients, can induce specific T cell sequestration at vaccination sites followed by dysfunction and deletion; short-lived depot formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.

ORGANISM(S): Mus musculus

PROVIDER: GSE43929 | GEO | 2013/03/02

SECONDARY ACCESSION(S): PRJNA188175

REPOSITORIES: GEO

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Studies in a murine B16 melanoma model show that persistent antigen at vaccination sites induces CD8+ T cell sequestration, dysfunction and deletion

Project description:To understand why cancer vaccine-induced T cells often fail to eradicate tumors, we studied immune responses in mice vaccinated with gp100 peptide emulsified in incomplete Freund's adjuvant (IFA), commonly used in clinical cancer vaccine trials. After gp100 peptide/IFA vaccination, tumor-specific CD8+ T cells (adoptively transferred from gp100-specific TCR-transgenic pmel-1 mice) accumulated not in tumors but at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, IFN-γ and FasL-mediated apoptosis, resulting in systemic hyporesponsiveness to subsequent vaccination. Provision of anti-CD40 antibody, TLR7 agonist and interleukin-2 (covax) reduced T cell apoptosis but did not prevent vaccination site sequestration. A non-persisting vaccine formulation shifted T cell localization towards tumors, inducing superior anti-tumor activity. Short-lived formulation also reduced systemic T cell dysfunction and promoted memory formation, as shown by gene expression profiling and other measures. Persisting peptide/IFA vaccine depots, currently used to vaccinate cancer patients, can induce specific T cell sequestration at vaccination sites followed by dysfunction and deletion; short-lived depot formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines. To study the fate of melanoma-specific CD8+ T cells after peptide vaccination, we tracked T cell receptor-transgenic pmel-1 T cells in mice vaccinated with heteroclitic gp100_25-33 peptide emulsified in IFA. Splenic pmel-1 CD8+ T cells were purified at 6 and 21 days after vaccination with either gp100/IFA/covax or gp100/saline/covax, and then their total RNA was extracted and used for comparison by gene expression profiling.

2013-03-02 | E-GEOD-43929 | biostudies-arrayexpress

Genome-wide analysis of gene expression in lymph nodes and vaccination site in mice vaccinated with adenovirus and MVA mixed formulations

2012-12-01 | GSE30564 | GEO

Genome-wide analysis of gene expression in lymph nodes and vaccination site in mice vaccinated with adenovirus and MVA mixed formulations

Project description:Gene expression analysis in lymph nodes and site of injection (intradermal) after vaccination with adenovirus (Ad), modified vaccinia Ankara (MVA) or a mixed formulation of Ad+MVA. The hypothesis tested in the present study was that co-administration of two viral vectors induce a differential gene expression in the site of vaccination (dermis) and the draining lymph nodes that ultimately influences the protective ability of a vaccine against pre-erythrocytic malaria. Total RNA was isolated from the vaccination site (dermis) and lymph nodes after vaccination with adenovirus, MVA or Ad+MVA mixed co-administration after 6h and 24h (ear biopsies) and 9h, 24h and 72h for lymph nodes. Differential gene expression was assessed between vaccinated and non-immunized mice. Four ear biopsy samples did not pass quality control, and are not included in this submission.

2012-12-01 | E-GEOD-30564 | biostudies-arrayexpress

Inhibition of Tumor Growth and Metastasis by EMMPRIN Multiple Antigenic Peptide (MAP) Vaccination Is Mediated by Immune Modulation

Project description:We report here that a EMMPRINs-specific cancer peptide vaccination, where the peptide was modified and synthesied as a multiple antigenic peptide (MAP), significantly inhibited tumor growth and metastases. Specifically, we describe changes in the gene expression profile as assessed by RNAseq in tumors derived from mice implanted with the colon tumorigenic carcinoma (CT26 cells), and vaccinated with either a control scrambled multiple antigenic peptide (Scr-MAP) or with an epitope-specific EMMPRIN multiple antigenic peptide (designated 161-MAP).

2019-08-06 | GSE85440 | GEO

VIA of EM CD8 T cells in vaccinated monkeys

Project description:The goal of an effective AIDS vaccine is to generate immunity that will prevent HIV-1 acquisition. Despite limited progress towards this goal, renewed optimism has followed the recent success of the RV144 vaccine trial in Thailand. However, the lack of complete protection in this trial suggests that breakthroughs, where infection occurs despite adequate vaccination, will be a reality for many vaccine candidates. We previously reported that neutralizing antibodies elicited by DNA prime/rAd5 boost vaccination with SIVmac239 Gag/Pol and Env provided protection against pathogenic SIVsmE660 acquisition after repeated mucosal challenge. Here, we report that SIV-specific CD8+ T cells elicited by that vaccine lowered both peak and set-point viral loads in macaques that became infected despite vaccination. These SIV-specific CD8+ T cells showed strong virus inhibitory activity (VIA) and displayed an effector memory (EM) phenotype. VIA correlated with high levels of CD107a mobilization and perforin expression in SIV-specific CD8+ T cells. Remarkably, both the frequency and the number of Gag CM9-specific public clonotypes were strongly correlated with VIA mediated by EM CD8+ T cells. The ability to elicit such virus-specific EM CD8+ T cells might contribute substantially to an efficacious HIV/AIDS vaccine, even after breakthrough infection. Gag CM9-specific EM CD8+ T cells (CD28 low CD95 high tetramer+) from SIV-negative macaques at 12 wks post-DNA/rAd5 immunization were sorted by flow cytometry for microarray studies. RNA samples from strong VIA animals with (n=3) or without (n=6) CM9 peptide stimulation, along with CM9 peptide stimulated samples from weak VIA animals (n=2) were prepared using the Illumina beads station assay and hybridized to the Illumina HumanHT-12 version 4 Expression BeadChip.

2012-06-14 | E-GEOD-35628 | biostudies-arrayexpress

Association of DNA-methylation profiles with immune responses in breast cancer patients

Project description:Immune response to a given antigen, particularly in cancer patients, is complex and is controlled by various genetic and environmental factors. Identifying biomarkers that can predict robust response to immunization is an urgent need in clinical cancer vaccine development. Given the involvement of DNA methylation in the development of lymphocytes, tumorigenicity and tumor progression, we aimed to analyze pre-vaccination DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) from breast cancer subjects vaccinated with a novel peptide-based vaccine referred to as P10s-PADRE.

| EGAS00001004211 | EGA

C5aR+ dendritic cells fine-tune the Peyer’s patch microenvironment to induce antigen-specific CD8+ T cells

Project description:The mucosa is an ideal route for vaccination against pathogen infection, but the effective adjuvant capable of overcoming the tolerogenic dendritic cell (DC) environment is unavailable. We characterized type 2 conventional DCs and lysozyme-expressing monocyte-derived DCs (LysoDCs) of Peyer’s patches to identify the vaccination target cells through single-cell RNA sequencing. Based on functional analysis of the data, we suggest that C5aR+ LysoDCs and Co1 peptide, a C5aR ligand, as a target cell and an adjuvant, respectively, for mucosal vaccination. Co1-mediated stimulation of C5aR+ LysoDCs increased the level of reactive oxygen species, leading to CCL3-mediated chemotaxis and exogenous antigen cross-presentation, which elicited an antigen-specific CD8+ T cell response. In a SARS-CoV-2 vaccine model, Co1 peptide increased the frequency of antigen-specific polyfunctional CD8+ T cells in systemic as well as mucosal compartments. Collectively, LysoDC activation by Co1 peptide potentiates vaccination efficiency by constructing an immunostimulatory environment in the mucosal immune inductive site.

2023-07-24 | GSE212701 | GEO

Neuropilin-1(NRP1) is a T cell memory checkpoint limiting long-term anti-tumor immunity

Project description:Transcriptomic analysis of NRP1 KO and WT donor pMel-T cells recovered from B16-gp100 tumors

2020-07-01 | GSE151494 | GEO

The antibody landscapes against Group 1 and 2 influenza virus hemagglutinin following AS03 and MF59 adjuvanted H5N1 vaccination (probing_2_iga)

Project description:Current seasonal and pre-pandemic influenza vaccines induce short-lived predominantly strain-specific and limited heterosubtypic responses. To better understand how vaccine adjuvants AS03 and MF59 may provide improved antibody responses to vaccination, we interrogated serum from subjects who received 2 doses of inactivated monovalent influenza A/Indonesia/05/2005 vaccine with or without AS03 or MF59 using hemagglutinin (HA) microarrays (NCT01317758 and NCT01317745). The arrays were designed to reflect both full length and globular head HA derived from 17 influenza A subtypes (H1 to H16 and H18) and influenza B strains. We observed significantly increased strain-specific and broad homo- and hetero-subtypic antibody responses with both AS03 and MF59 adjuvanted vaccination with AS03 achieving a higher titer and breadth of IgG responses relative to MF59. Adjuvanted vaccine was also associated with the elicitation of stalk directed antibody. We established good correlation of the array antibody responses to H5 antigens with standard HA inhibition and microneutralization titers.

2022-07-01 | GSE202383 | GEO

The antibody landscapes against Group 1 and 2 influenza virus hemagglutinin following AS03 and MF59 adjuvanted H5N1 vaccination (probing_3_igg)

2022-07-01 | GSE202388 | GEO

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