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Genome-wide analysis of genes induced in TRAMP mouse prostate tumors after Mobilan injection

ABSTRACT: Toll-like receptor 5 is considered an attractive target for anticancer immunotherapy. TLR5 agonists, bacterial flagellin and engineered flagellin derivatives, have been shown to have potent anti-tumor and metastasis-suppressive effects in multiple animal models and to be safe in both animals and humans. Anticancer efficacy of TLR5 agonists stems from TLR5-dependent activation of NF-kB that mediates innate and adaptive anti-tumor immune responses. To extend application of TLR5-targeted anticancer immunotherapy to tumors that do not naturally express TLR5, we created an adenovirus-based vector for intratumor delivery, named Mobilan that drives expression of self-activating TLR5 signaling cassette comprising of human TLR5 and a secreted derivative of Salmonella flagellin structurally analogous to a clinical stage TLR5 agonist, entolimod. Co-expression of TLR5 receptor and agonist in Mobilan-infected cells established an autocrine/paracrine TLR5 signaling loop resulting in constitutive activation of NF-kB both in vitro and in vivo. Injection of Mobilan into primary tumors of the prostate cancer-prone TRAMP mice resulted in a strong induction of multiple genes involved in inflammatory responses and mobilization of innate immune cells into the tumors including neutrophils and NK cells and suppressed tumor progression. Intratumoral injection of Mobilan into subcutaneously-growing syngeneic prostate tumors in immunocompetent hosts improved animal survival after surgical resection of the tumors, by suppression of tumor metastasis. In addition, vaccination of mice with irradiated Mobilan-transduced prostate tumor cells protected mice against subsequent tumor challenge. These results provide proof-of-concept for Mobilan as a tool for antitumor vaccination that directs TLR5-mediated immune response towards cancer cells and does not require identification of tumor antigens.

ORGANISM(S): Mus musculus

PROVIDER: GSE102023 | GEO | 2017/07/29

SECONDARY ACCESSION(S): PRJNA396227

REPOSITORIES: GEO

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Project description:Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. Pre-clinical studies demonstrate that toll-like receptor (TLR) agonists can enhance the anti-tumor immune response from cancer vaccines. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a randomized, open-label multi-arm Phase 2 clinical trial to evaluate immune responses and survival in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. Patients were randomized to receive ATL-DC vaccination with either a placebo, a TLR-7/8 agonist (resiquimod, topical 0.2%), or a TLR-3 agonist (poly-ICLC, 20 mcg/kg intramuscular). Peripheral blood was obtained at baseline and following the vaccination cycle for immune monitoring. Mass cytometry, bulk and single-cell RNA sequencing analyses were performed. Analysis of the bulk RNAseq data (pre-treatment vs. post-treatment) demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant TLR agonist (either poly-ICLC or resiquimod) together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased levels of memory PD-1+ T-cell and monocyte populations after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Median progression-free survival (PFS) was 8.1 months (5.5 placebo vs. 8.1 resiquimod vs. 31.4 poly-ICLC), and median overall survival (OS) was 26.6 months (7.7 placebo vs. 16.7 resiquimod vs. 52.5 poly-ICLC). Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLCTL induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population. This combination was associated with extended survival in this patient population. This interferon response signature may represent an important blood biomarker for immunotherapy in patients with malignant glioma.

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Genome-wide analysis of genes induced in TRAMP mouse prostate tumors after Mobilan injection

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