Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy

Abstract

The delivery of stimulatory signals to dendritic cells (DCs) in the tumor microenvironment could be an effective means to break tumorinduced tolerance. The work presented here evaluates the immunostimulatory properties of pathogen-associated molecular patterns (PAMPs), microbial molecules which bind Toll-like receptors and deliver activating signals to immune cells, when expressed in tumor cells using adenoviral (Ad) vectors. In vitro, transduction of A549 tumor cells with Ad vectors expressing either flagellin from Listeria monocytogenes or P40 protein from Klebsiella pneumoniae induced the maturation of human monocyte-derived DCs in co-cultures. In mixed lymphocyte reactions (MLRs), Ad-flagellin and Ad-P40 transduction of tumor cells stimulated lymphocyte proliferation and the secretion of IFN-g. In vivo, these vectors were used either as stand-alone immunoadjuvants injected intratumorally or as vaccine adjuvants combined with a tumor antigen-expressing vector. When Ad-PAMPs were administered intratumorally to mice bearing subcutaneous syngeneic B16F0-CAR (cocksackie-adenovirus receptor) melanomas, tumor progression was transiently inhibited by Ad-P40. In a therapeutic vaccine setting, the combination of Ad-MUC1 and Ad-PAMP vectors injected subcutaneously delayed the growth of implanted RenCa-MUC1 tumors and improved tumor rejection when compared with vaccination with Ad-MUC1 alone. These results suggest that Ad-PAMPs could be effective immunoadjuvants for cancer immunotherapy.

The Adjuvant Activity of Alphavirus Replicons Is Enhanced by Incorporating the Microbial Molecule Flagellin into the Replicon

“…Dendritic cells are activated and matured by flagellin administered in its soluble form [13] or expressed from a viral vector, as has been demonstrated with paramyxovirus simian virus 5 [14], adenovirus [15] and vesicular stomatitis virus [16]. Due to these properties, flagellin has been investigated for use as an adjuvant and has been shown to induce enhanced antigen-specific antibody responses as well as CD4+ and CD8+ T cell responses in animal models [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27].…”

TLR Stimulation of Prostate Tumor Cells Induces Chemokine-Mediated Recruitment of Specific Immune Cell Types

“…To our knowledge, this is the first demonstration that the PCa cells LNCaP and DU-145 express TLR5, suggesting that this receptor might be exploited as a therapeutic target. In this regard, the potential role of flagellin in activating an immune response in cancer immunotherapy is under investigation in melanoma and renal carcinoma (53).…”

Cancer immunogenicity, danger signals, and DAMPs: What, when, and how?

“…Cancer cells artificially made to express PAMPs ( e.g . flagellin from Listeria monocytogenes or P40 from Klebsiella pneumoniae ) may induce anti‐tumor immunological response, an evidence that strongly vouches for a role of PRRs‐PAMPs/DAMPs interactions in regulating cancer cell's immunogenicity . However, does this mean that the host immune system treats DAMPs in the same exact way as PAMPs?…”