Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice

Ying Wang, Lijing Su, Matthew D. Morin, Brian T. Jones, Yuto Mifune, Hexin Shi, Kuan wen Wang, Xiaoming Zhan, Aijie Liu, Jianhui Wang, Xiaohong Li, Miao Tang, Sara Ludwig, Sara Hildebrand, Kejin Zhou, Daniel J. Siegwart, Eva Marie Y. Moresco, Hong Zhang, Dale L. Boger, Bruce Beutler

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Successful cancer immunotherapy entails activation of innate immune receptors to promote dendritic cell (DC) maturation, antigen presentation, up-regulation of costimulatory molecules, and cytokine secretion, leading to activation of tumor antigen-specific cytotoxic T lymphocytes (CTLs). Here we screened a synthetic library of 100,000 compounds for innate immune activators using TNF production by THP-1 cells as a readout. We identified and optimized a potent human and mouse Toll-like receptor (TLR)1/TLR2 agonist, Diprovocim, which exhibited an EC50 of 110 pM in human THP-1 cells and 1.3 nM in primary mouse peritoneal macrophages. In mice, Diprovocim-adjuvanted ovalbumin immunization promoted antigen-specific humoral and CTL responses and synergized with anti–PD-L1 treatment to inhibit tumor growth, generating long-term antitumor memory, curing or prolonging survival of mice engrafted with the murine melanoma B16-OVA. Diprovocim induced greater frequencies of tumor-infiltrating leukocytes than alum, of which CD8 T cells were necessary for the antitumor effect of immunization plus anti–PD-L1 treatment.

Original languageEnglish (US)
Pages (from-to)E8698-E8706
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number37
DOIs
StatePublished - Sep 11 2018

Fingerprint

Melanoma
Cytotoxic T-Lymphocytes
Immunization
Toll-Like Receptor 1
Neoplasms
Experimental Melanomas
Long-Term Memory
Ovalbumin
Antigen Presentation
Peritoneal Macrophages
Neoplasm Antigens
Immunotherapy
Dendritic Cells
Leukocytes
Up-Regulation
Cytokines
T-Lymphocytes
Antigens
Therapeutics
Growth

Keywords

  • Agonist
  • Cancer immunotherapy
  • Melanoma
  • PD-L1 antibody
  • TLR1/TLR2

ASJC Scopus subject areas

  • General

Cite this

Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice. / Wang, Ying; Su, Lijing; Morin, Matthew D.; Jones, Brian T.; Mifune, Yuto; Shi, Hexin; Wang, Kuan wen; Zhan, Xiaoming; Liu, Aijie; Wang, Jianhui; Li, Xiaohong; Tang, Miao; Ludwig, Sara; Hildebrand, Sara; Zhou, Kejin; Siegwart, Daniel J.; Moresco, Eva Marie Y.; Zhang, Hong; Boger, Dale L.; Beutler, Bruce.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 37, 11.09.2018, p. E8698-E8706.

Research output: Contribution to journalArticle

Wang, Ying ; Su, Lijing ; Morin, Matthew D. ; Jones, Brian T. ; Mifune, Yuto ; Shi, Hexin ; Wang, Kuan wen ; Zhan, Xiaoming ; Liu, Aijie ; Wang, Jianhui ; Li, Xiaohong ; Tang, Miao ; Ludwig, Sara ; Hildebrand, Sara ; Zhou, Kejin ; Siegwart, Daniel J. ; Moresco, Eva Marie Y. ; Zhang, Hong ; Boger, Dale L. ; Beutler, Bruce. / Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 37. pp. E8698-E8706.
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abstract = "Successful cancer immunotherapy entails activation of innate immune receptors to promote dendritic cell (DC) maturation, antigen presentation, up-regulation of costimulatory molecules, and cytokine secretion, leading to activation of tumor antigen-specific cytotoxic T lymphocytes (CTLs). Here we screened a synthetic library of 100,000 compounds for innate immune activators using TNF production by THP-1 cells as a readout. We identified and optimized a potent human and mouse Toll-like receptor (TLR)1/TLR2 agonist, Diprovocim, which exhibited an EC50 of 110 pM in human THP-1 cells and 1.3 nM in primary mouse peritoneal macrophages. In mice, Diprovocim-adjuvanted ovalbumin immunization promoted antigen-specific humoral and CTL responses and synergized with anti–PD-L1 treatment to inhibit tumor growth, generating long-term antitumor memory, curing or prolonging survival of mice engrafted with the murine melanoma B16-OVA. Diprovocim induced greater frequencies of tumor-infiltrating leukocytes than alum, of which CD8 T cells were necessary for the antitumor effect of immunization plus anti–PD-L1 treatment.",
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