Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
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 EC 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.
成功的癌症免疫疗法需要激活先天免疫受体，以促进树突状细胞 (DC) 的成熟、抗原呈递、共刺激分子的上调和细胞因子的分泌，从而激活肿瘤抗原特异性细胞毒性 T 淋巴细胞 (CTL)。在这里，我们使用 THP-1 细胞产生 TNF 作为读数，筛选了 100,000 种化合物的合成文库，以寻找先天免疫激活剂。我们鉴定和优化了一种有效的人类和小鼠 Toll 样受体 (TLR)1/TLR2 激动剂 Diprovocim，其在人类 THP-1 细胞中的 EC 为 110 pM，在原代小鼠腹腔巨噬细胞中的 EC 为 1.3 nM。在小鼠中，Diprovocim 佐剂卵清蛋白免疫可促进抗原特异性体液和 CTL 反应，并与抗 PD-L1 治疗协同抑制肿瘤生长，产生长期抗肿瘤记忆，治愈或延长荷瘤小鼠的存活期，这些小鼠植入了鼠黑色素瘤 B16-OVA。Diprovocim 诱导的肿瘤浸润白细胞频率高于明矾，其中 CD8 T 细胞是免疫接种加抗 PD-L1 治疗抗肿瘤作用所必需的。
