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

Proceedings of the National Academy of Sciences of the United States of America
Ying WangBruce Beutler

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.

References

Feb 1, 1994·The Journal of Experimental Medicine·L ChenK E Hellström
Jan 24, 2002·Journal of the American Chemical Society·Joel GoldbergDale L Boger
Sep 6, 2007·Science's STKE : Signal Transduction Knowledge Environment·Heather MacLeod, Lee M Wetzler
Sep 2, 2008·Blood·Bruce A Beutler
May 28, 2010·The Journal of Biological Chemistry·Yue GuanRichard I Tapping
Oct 30, 2010·Immunity·Robert L CoffmanRobert A Seder
Jan 11, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yi ZhangYiwei Chu
Jul 22, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Mukanthu H NyirendaBruno Gran
Jan 4, 2013·Cold Spring Harbor Perspectives in Biology·Kian-Huat Lim, Louis M Staudt
Dec 7, 2013·Nature Medicine·Steven G ReedChristopher B Fox
Apr 1, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kuan-Yin ShenShih-Jen Liu
Oct 14, 2014·Frontiers in Immunology·Takumi Kawasaki, Taro Kawai
Apr 11, 2015·Cancer Cell·Suzanne L TopalianDrew M Pardoll
Jun 29, 2016·Clinical & Translational Immunology·Jennifer K Dowling, Ashley Mansell
Oct 9, 2016·Methods in Molecular Biology·Ruchi R ShahLuis A Brito
Nov 2, 2016·Proceedings of the National Academy of Sciences of the United States of America·Shu WangCristiana Guiducci
Feb 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Hua WangZhijian J Chen
Feb 12, 2017·Cell·Padmanee SharmaAntoni Ribas
Jul 25, 2017·Biochimica Et Biophysica Acta. General Subjects·M S MurgueitioS Santos-Sierra

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Citations

Sep 25, 2018·Chemical Communications : Chem Comm·Zhipeng ChenKui Cheng
Sep 5, 2019·Journal of Clinical Medicine·Na-Ra HanHyun-Ja Jeong
Nov 9, 2019·Chembiochem : a European Journal of Chemical Biology·Hong-Guo HuYan-Mei Li
Nov 16, 2019·Journal for Immunotherapy of Cancer·Hans-Georg RammenseeMarkus W Löffler
Feb 11, 2020·Chemical Society Reviews·Jingying LiHuanghao Yang
Nov 30, 2019·Biological Chemistry·Sandra Santos-Sierra
May 27, 2020·Acta Pharmacologica Sinica·Simon Van Herck, Bruno G De Geest
Jul 20, 2020·International Journal of Cancer. Journal International Du Cancer·Xiaodong WangGuangyi Jin
Aug 28, 2020·Frontiers in Chemistry·Hong-Guo Hu, Yan-Mei Li
May 29, 2020·Journal for Immunotherapy of Cancer·Seongmin ChoSunghoon Kim
Aug 3, 2019·International Journal of Molecular Sciences·Stephen JiangMing Q Wei
Jan 16, 2021·Drug Discovery Today·Sandeep KumarAjay Rana
Dec 17, 2020·International Journal of Molecular Sciences·Antonino Di LorenzoLaura Conti
Feb 19, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Fanglin HeRenbing Jia
Feb 19, 2021·Journal of Cell Science·Miao Li, Yan Yu
May 29, 2021·Journal of Medicinal Chemistry·Zhisong WangXuebin Liao
Jul 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Lijing SuBruce Beutler
Dec 22, 2020·Journal of Medicinal Chemistry·Arshpreet KaurDeepak B Salunke
Mar 5, 2019·Journal of Medicinal Chemistry·Lijing SuHong Zhang
Sep 12, 2020·Chemical Reviews·Wen-Hao Li, Yan-Mei Li
Oct 3, 2018·Journal of the American Chemical Society·Matthew D MorinDale L Boger
Aug 24, 2021·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Anindya SarkarDale L Boger
May 15, 2021·Science Signaling·Michael G McCoyTatiana V Byzova
Oct 31, 2021·Journal of Hematology & Oncology·Yang XunHua You
Mar 3, 2020·Advanced Drug Delivery Reviews·Livia Neves Borgheti-CardosoMaria Vitória Lopes Badra Bentley

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