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Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice
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Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice
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Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice
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Journal Article
Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice
2018
Overview
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.
Publisher
National Academy of Sciences
Subject
Adjuvants, Immunologic - pharmacology
/ Animals
/ Antibodies, Monoclonal - immunology
/ Antibodies, Monoclonal - pharmacology
/ B7-H1 Antigen - antagonists & inhibitors
/ Cancer
/ Humans
/ Melanoma
/ Melanoma, Experimental - genetics
/ Melanoma, Experimental - immunology
/ Melanoma, Experimental - therapy
/ Mice
/ Proteins
/ 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
/ Tumors
