Abstract
Although critical for initiating and regulating immune responses, the therapeutic use of individual cytokines as anticancer immunotherapeutic agents has achieved only modest clinical success. Consequently, many current strategies have focused on the use of specific immunotherapeutic agonists that engage individual receptors of innate immune networks, such as the Toll-like receptor (TLR) system, each resulting in specific patterns of gene expression, cytokine production, and inflammatory outcome. However, these immunotherapeutics are constrained by variable cellular TLR expression and responsiveness to particular TLR agonists, as well as the specific cellular context of different tumors. We hypothesized that overexpression of MyD88, a pivotal regulator of multiple TLR signaling pathways, could circumvent these constraints and mimic coordinated TLR signaling across all cell types in a ligand-independent fashion. To explore this hypothesis, we generated an adenoviral vector expressing MyD88 and show that Ad-MyD88 infection elicits extensive Th1-specific transcriptional and secreted cytokine signatures in all murine and human cell types tested in vitro and in vivo. Importantly, in vivo intratumoral injection of Ad-MyD88 into established tumor masses enhanced adaptive immune responses and inhibited local tumor immunosuppression, resulting in significantly inhibited local and systemic growth of multiple tumor types. Finally, Ad-MyD88 infection of primary human dendritic cells, tumor-associated fibroblasts, and colorectal carcinoma cells elicited significant Th1-type cytokine responses, resulting in enhanced tumor cell lysis and expansion of human tumor antigen-specific T cells. Thus, Ad-MyD88 initiated robust antitumor activity in established murine tumor microenvironments and in human contexts, suggesting its potential effectiveness as a clinical immunotherapeutic strategy.
Highlights
Immunotherapy strategies either frequently target single tumor antigens or, alternatively, nonspecifically induce antitumor immunity through nonspecific approaches, such as the systemic delivery of purified cytokines [1, 2]
We first investigated the transcriptional effect of Admediated mouse MyD88 overexpression on mouse bone marrow–derived dendritic cells (DC)
When all differences between control- and Ad-MyD88– infected mouse embryonic fibroblasts (MEF) and bone marrow–derived DCs (bmDC) were assessed together by oneway ANOVA (P = 0.05 with Benjamini and Hochberg multiple testing correction), it was revealed that ∼8.0% of the total transcriptome was dysregulated by MyD88 overexpression
Summary
Immunotherapy strategies either frequently target single tumor antigens or, alternatively, nonspecifically induce antitumor immunity through nonspecific approaches, such as the systemic delivery of purified cytokines [1, 2]. The development of gene transfer techniques has expanded focus on individual effector cytokine, chemokine, or receptor genes delivered to specific tissues, such as granulocyte macrophage. Authors' Affiliations: 1Department of Surgery and Comprehensive Cancer Center and 2Department of Immunology, Duke University Medical Center, Durham, North Carolina. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Microarray data were submitted to the National Center for Biotechnology Information's Gene Expression Omnibus Web site Duke University Medical Center, Research Drive, MSRB I, Box 2606, Durham, NC 27710. Phone: 919-684-0350; Fax: 919-681-7970; E-mail: tim.clay@ duke.edu
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