Effective cancer immunotherapy based on combination of TLR agonists with stimulation of phagocytosis
Effective cancer immunotherapy based on combination of TLR agonists with stimulation of phagocytosis
复制标题
DOI：
10.1016/j.intimp.2018.03.038
复制
发表时间：
2018-06-01
影响因子：
5.6
通讯作者：
Zenka, Jan
中科院分区：
文献类型：
--
作者：
Caisova, Veronika;Uher, Ondrej;Zenka, Jan
免疫疗法成为癌症治疗的基本方法。迄今为止，已经评估了许多不同免疫疗法的功效。使用微生物或其部分用于免疫细胞活化，称为病原体相关分子模式（PAMP），代表了非常有前途的概念。PAMP的治疗效果可以通过不同类型的PAMP如Toll样受体（TLR）激动剂和吞噬激活配体的适当组合来进一步放大。先前，我们使用吞噬活化配体（甘露聚糖）和TLR激动剂（瑞喹莫特（R-848）、聚（I：C）、灭活的单核细胞增生李斯特菌）的混合物的组合来成功治疗鼠B16-F10模型中的黑素瘤。在本研究中，我们优化了先前使用的混合物的组成和时间。基于明确定义的化合物的治疗混合物由甘露聚糖通过生物相容性膜用锚（BAM）和TLR激动剂瑞喹莫特、聚（I：C）和脂磷壁酸（LTA）锚定到肿瘤细胞表面组成。优化导致（1）在83%的小鼠中根除晚期进行性黑色素瘤，（2）获得对肿瘤再移植的抗性，和（3）潜在的抗转移作用。在进一步研究机制、潜在的抗肿瘤反应后，我们得出结论，先天性和适应性免疫都被激活并参与这些过程。我们还在侵袭性胰腺肿瘤Panc 02小鼠模型中测试了我们的治疗效果。同时应用激动性抗CD 40抗体是必要的，以达到有效的治疗反应（80%的回收率），在这个model.Our结果表明，本文提出的免疫治疗方法是一个有前途的癌症治疗策略，不仅能够根除原发性肿瘤，但也转移。
Immunotherapy emerges as a fundamental approach in cancer treatment. Up to date, the efficacy of numerous different immunotherapies has been evaluated. The use of microorganisms or their parts for immune cell activation, referred to as Pathogen-Associated Molecular Patterns (PAMPs), represents highly promising concept. The therapeutic effect of PAMPs can be further amplified by suitable combination of different types of PAMPs such as Toll like receptor (TLR) agonists and phagocytosis activating ligands. Previously, we used the combination of phagocytosis activating ligand (mannan) and mixture of TLR agonists (resiquimod (R-848), poly(I:C), inactivated Listeria monocytogenes) for successful treatment of melanoma in murine B16-F10 model. In the present study, we optimized the composition and timing of previously used mixture. Therapeutic mixture based on well-defined chemical compounds consisted of mannan anchoring to tumor cell surface by biocompatible anchor for membranes (BAM) and TLR agonists resiquimod, poly(I:C), and lipoteichoic acid (LTA). The optimization resulted in (1) eradication of advanced stage progressive melanoma in 83% of mice, (2) acquisition of resistance to tumor re-transplantation, and (3) potential anti-metastatic effect. After further investigation of mechanisms, underlying anti-tumor responses, we concluded that both innate and adaptive immunity are activated and involved in these processes.We tested the efficacy of our treatment in Panc02 murine model of aggressive pancreatic tumor as well. Simultaneous application of agonistic anti-CD40 antibody was necessary to achieve effective therapeutic response (80% recovery) in this model.Our results suggest that herein presented immunotherapeutic approach is a promising cancer treatment strategy with the ability to eradicate not only primary tumors but also metastases.