Dataset Information

Adenoviral based-vaccine promotes neoantigen specific CD8+ T cell stemness and tumor rejection

ABSTRACT: Upon chronic antigen exposure, CD8+ T cells become exhausted acquiring a dysfunctional state correlated with the inability to control infection or tumor. In contrast to exhausted T cells, stem-like CD8+ T progenitors maintain the ability to promote and sustain effective immunity. Adenovirus (Ad) vectored vaccines encoding tumor neoantigens have been shown to eradicate large tumors when combined with anti-Programmed cell death protein 1 (αPD-1) in murine models, however the mechanisms and translational potential have not yet been elucidated. Here, we show that gorilla Ad vaccine targeting tumor neoepitopes enhance responses to αPD-1 therapy, by improving immunogenicity and anti-tumor efficacy. Single cell RNA-seq demonstrated that the combination of Ad vaccine and αPD-1 increased the number of murine polyfunctional neoantigen specific CD8+ T cells over αPD-1 monotherapy, with an accumulation of Tcf1+ stem-like progenitors in draining lymph nodes and effector CD8+T cells in tumors. Combined TCR sequencing analysis highlighted a broader spectrum of neoantigen specific CD8+ T cells upon vaccination compared to αPD-1 monotherapy. The translational relevance of these data is supported by results obtained in the first 12 patients with metastatic deficient mismatch repair (dMMR) tumors vaccinated with an Ad vaccine encoding shared neoantigens. Expansion and diversification of TCRs was observed in post-treatment biopsies of patients with clinical response, as well as an increase in tumor infiltrating T cells with an effector memory signature. These findings indicate a promising mechanism to overcome resistance to PD-1 blockade, by promoting immunogenicity and broadening the spectrum and magnitude of neoantigen-specific T cells infiltrating tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE206811 | GEO | 2022/10/11

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Background. Dendritic cell (DC)-based neoantigen vaccination holds potential as a safe and effective adjuvant therapy for patients with early-stage, resectable NSCLC, a tumor type typically characterized by high mutational loads. DCs have the unique ability to elicit robust antitumoral T-cell responses, while neoantigens are ideal targets to elicit high-affinity T cell responses with exquisite tumor specificity. Here, we present the results of a phase I clinical trial in which a novel DC vaccine targeting neoantigens was evaluated in six patients with early stage, resected NSCLC. Methods. Tumor samples were subjected to a comprehensive neoantigen identification approach encompassing genomics, transcriptomics and immunopeptidomics. Using genomics and transcriptopmics data, tumor-specific antigens were identified by a bioinformatics approach. Additionally, immunopeptidomics was performed by immunoprecipitation of human MHC class I molecule followed by immunopeptides enrichment and LC-MS/MS analysis. Two immunopeptidomics screens were performed. In the first immunopeptidomics screen, patient-derived tumors were analyzed to uncover neoepitopes specific for the patient. In the second, screen, patient-derived EBV-immortilized B cell lines overexpressing the selected neoepitopes were analyzed to verify that the predicted neoepitopes can bind to the HLA haplotypes of the patients. For anti-tumor vaccination, patients underwent leukapheresis for the manufacturing of monocyte-derived DCs loaded with neoantigens (Neo-mDCs) according to a four-day protocol. Neo-mDCs were injected intravenously following an intrapatient dose escalation scheme. Primary endpoint of the trial was safety. Secondary endpoints were feasibility, immunogenicity, and relapse-free survival. Results. In the first immunopeptidomics screen, one neoepitopes derived was identified from the tumor of one patient. In the second immunopeptidomics screen, several predicted neoepitopes were confirmed to be presented on the HLA haplotypes of the patients by analyzing the patient-derived EBV-immortilized B cell lines. Additionally, the vaccine was demonstrated to be feasible and safe. T cell responses were observed in 5 of 6 vaccinated patients and were dominated by CD8+ T cells, which could be detected ex vivo at high frequencies >1.5 years after the last dose. Furthermore, single cell analysis indicated that the CD8+ T cell responsive population was polyclonal and exhibited the near entire spectrum of T cell differentiation states, including a naïve-like state associated with long lasting memory but excluding exhausted cell states. Three of six vaccinated patients experienced disease relapse. Conclusion. Neo-mDC vaccination is safe and feasible. Vaccination induces large populations of neoantigen-specific T-cell responses containing long lasting memory and effector cells in early-stage NSCLC patients, suggesting clinical potential.

Dataset Information

Adenoviral based-vaccine promotes neoantigen specific CD8+ T cell stemness and tumor rejection

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure