Manna Saikat, Maiti Sampa, Shen Jingjing, Du Wenjun, Esser-Kahn Aaron P
Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States.
Department of Chemistry and Biochemistry, Science of Advanced Material, Central Michigan University, Mount Pleasant, Michigan 48858, United States.
ACS Cent Sci. 2020 Nov 25;6(11):2071-2078. doi: 10.1021/acscentsci.0c01001. Epub 2020 Oct 27.
Therapies based on Toll Like Receptor agonists (TLRa) are emerging as a promising modality for cancer immunotherapy to recruit antitumor T-cells in unresponsive immunologically "cold" tumors. Often, combinations of agonists are employed to synergistically enhance efficacy. However, low efficacy and severe toxicities deter these TLR-based therapeutics from further clinical applications. Studies have suggested that the rapid systemic diffusion of agonists to nontarget tissues is the primary cause. To address this challenge, we developed supramolecular nanotherapeutics of covalently linked TLRas for multivalent, synergistic interactions by drawing inspiration from immune recognition of pathogens. This new nanotherapeutic increased stimulation of key pro-inflammatory cytokines and remarkably enhanced CD8 and NK cell-mediated antitumor response while exhibiting ultralow off-target toxicity in an aggressive B16.F10 tumor model. Results from our studies thereby indicate that such supramolecular immune-agonist therapeutics may be further developed as a viable treatment modality for cancer immunotherapy.
基于Toll样受体激动剂（TLRa）的疗法正在成为一种有前景的癌症免疫治疗方式，用于在免疫反应迟钝的“冷”肿瘤中募集抗肿瘤T细胞。通常，会使用激动剂组合来协同增强疗效。然而，低疗效和严重毒性阻碍了这些基于TLR的疗法进一步应用于临床。研究表明，激动剂快速向非靶组织的全身扩散是主要原因。为应对这一挑战，我们从病原体的免疫识别中获得灵感，开发了共价连接TLRa的超分子纳米疗法，以实现多价协同相互作用。这种新型纳米疗法增加了对关键促炎细胞因子的刺激，显著增强了CD8和NK细胞介导的抗肿瘤反应，同时在侵袭性B16.F10肿瘤模型中表现出超低的脱靶毒性。我们的研究结果表明，这种超分子免疫激动剂疗法可能会进一步发展成为一种可行的癌症免疫治疗方式。
