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Ligand-independent toll-like receptor signals generated by ectopic overexpression of MyD88 generate local and systemic antitumor immunity.

Publication ,  Journal Article
Hartman, ZC; Osada, T; Glass, O; Yang, XY; Lei, G-J; Lyerly, HK; Clay, TM
Published in: Cancer Res
September 15, 2010

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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 15, 2010

Volume

70

Issue

18

Start / End Page

7209 / 7220

Location

United States

Related Subject Headings

  • Toll-Like Receptors
  • T-Lymphocytes
  • Signal Transduction
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Myeloid Differentiation Factor 88
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
 

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Hartman, Z. C., Osada, T., Glass, O., Yang, X. Y., Lei, G.-J., Lyerly, H. K., & Clay, T. M. (2010). Ligand-independent toll-like receptor signals generated by ectopic overexpression of MyD88 generate local and systemic antitumor immunity. Cancer Res, 70(18), 7209–7220. https://doi.org/10.1158/0008-5472.CAN-10-0905
Hartman, Zachary C., Takuya Osada, Oliver Glass, Xiao Y. Yang, Gang-Jun Lei, H Kim Lyerly, and Timothy M. Clay. “Ligand-independent toll-like receptor signals generated by ectopic overexpression of MyD88 generate local and systemic antitumor immunity.Cancer Res 70, no. 18 (September 15, 2010): 7209–20. https://doi.org/10.1158/0008-5472.CAN-10-0905.
Hartman ZC, Osada T, Glass O, Yang XY, Lei G-J, Lyerly HK, et al. Ligand-independent toll-like receptor signals generated by ectopic overexpression of MyD88 generate local and systemic antitumor immunity. Cancer Res. 2010 Sep 15;70(18):7209–20.
Hartman, Zachary C., et al. “Ligand-independent toll-like receptor signals generated by ectopic overexpression of MyD88 generate local and systemic antitumor immunity.Cancer Res, vol. 70, no. 18, Sept. 2010, pp. 7209–20. Pubmed, doi:10.1158/0008-5472.CAN-10-0905.
Hartman ZC, Osada T, Glass O, Yang XY, Lei G-J, Lyerly HK, Clay TM. Ligand-independent toll-like receptor signals generated by ectopic overexpression of MyD88 generate local and systemic antitumor immunity. Cancer Res. 2010 Sep 15;70(18):7209–7220.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 15, 2010

Volume

70

Issue

18

Start / End Page

7209 / 7220

Location

United States

Related Subject Headings

  • Toll-Like Receptors
  • T-Lymphocytes
  • Signal Transduction
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Myeloid Differentiation Factor 88
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C