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. Epub 2018 Aug 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / immunology
  • Cell Line, Tumor
  • Cells, Cultured
  • Drug Synergism
  • Humans
  • Immunotherapy / methods
  • Kaplan-Meier Estimate
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Ovalbumin / immunology
  • THP-1 Cells
  • Toll-Like Receptor 1 / agonists*
  • Toll-Like Receptor 1 / genetics
  • Toll-Like Receptor 1 / metabolism
  • Toll-Like Receptor 2 / agonists*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism


  • Adjuvants, Immunologic
  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • Ovalbumin