2. Academic Validation
  3. Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti-PD-L1 to eliminate melanoma in mice

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

  • Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8698-E8706. doi: 10.1073/pnas.1809232115.
Ying Wang 1,  Lijing Su 1,  Matthew D Morin 2,  Brian T Jones 2,  Yuto Mifune 2,  Hexin Shi 1,  Kuan-Wen Wang 1,  Xiaoming Zhan 1,  Aijie Liu 1,  Jianhui Wang 1,  Xiaohong Li 1,  Miao Tang 1,  Sara Ludwig 1,  Sara Hildebrand 1,  Kejin Zhou 3 4,  Daniel J Siegwart 3 4,  Eva Marie Y Moresco 1,  Hong Zhang 1,  Dale L Boger 2,  Bruce Beutler 5
Affiliations

Affiliations

  • 1 Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 2 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
  • 3 Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 5 Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; bruce.beutler@utsouthwestern.edu.
PMID: 30150374 DOI: 10.1073/pnas.1809232115
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.

Keywords

PD-L1 antibody; TLR1/TLR2; agonist; cancer immunotherapy; melanoma.

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