Costimulation as a platform for the development of vaccines: a peptide-based vaccine containing a novel form of 4-1BB ligand eradicates established tumors.
Costimulation as a platform for the development of vaccines: a peptide-based vaccine containing a novel form of 4-1BB ligand eradicates established tumors.
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DOI：
10.1158/0008-5472.can-08-3141
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发表时间：
2009-05-15
期刊：
影响因子：
11.2
通讯作者：
Shirwan H
中科院分区：
文献类型：
--
作者：
Sharma RK;Elpek KG;Yolcu ES;Schabowsky RH;Zhao H;Bandura-Morgan L;Shirwan H
疫苗是治疗癌症的一种有吸引力的治疗方式，主要是因为它们的特异性和免疫记忆的产生对控制复发很重要。然而，治疗性疫苗的功效可能需要配方不仅产生有效的免疫反应，而且还克服进展性肿瘤所采用的免疫逃避机制。共刺激分子在调节先天免疫、适应性免疫和调节性免疫中发挥关键作用，并有可能作为治疗性疫苗的有效免疫调节成分。在这项研究中，我们测试了一种新的可溶性形式的4-1BBL共刺激分子在调节先天、适应性和调节性免疫中的功能，并评估了其在表达HPV-16 e7的TC-1宫颈癌和表达survivin的3LL肺癌小鼠模型中的治疗效果。接种4-1BBL可激活dc并增强抗原摄取，产生CD8+ T细胞效应/记忆反应，并赋予T效应细胞抵抗CD4+CD25+FoxP3+ T调节细胞的抑制。4-1BBL与E7肽或survivin蛋白联合免疫分别可根除TC-1和3LL肿瘤。4-1BBL比TLR激动剂LPS、MPL、CpG和一种激动剂4-1BB Ab作为E7肽基治疗性疫苗的组成部分，在没有可检测到的毒性的情况下产生免疫应答和根除TC-1建立的肿瘤更有效。治疗效果与肿瘤介导的无反应性/能量的逆转以及CD8+ T细胞长期记忆的建立有关。4-1BBL分子具有强大的多效性免疫调节活性，且无毒性，这表明它有可能成为治疗性癌症疫苗的有效成分。
Vaccines represent an attractive treatment modality for the management of cancer primarily because of their specificity and generation of immunological memory important for controlling recurrences. However, the efficacy of therapeutic vaccines may require formulations that not only generate effective immune responses, but also overcome immune evasion mechanisms employed by progressing tumor. Costimulatory molecules play critical roles in modulating innate, adaptive, and regulatory immunity, and have potential to serve as effective immunomodulatory components of therapeutic vaccines. In this study, we tested the function of a novel soluble form of 4-1BBL costimulatory molecule in modulating innate, adaptive, and regulatory immunity, and assessed its therapeutic efficacy in the HPV-16 E7-expressing TC-1 cervical cancer and survivin-expressing 3LL lung carcinoma mouse models. Vaccination with 4-1BBL activated DCs and enhanced antigen uptake, generated CD8+ T cell effector/memory responses, and endowed T effector cells refractory to suppression by CD4+CD25+FoxP3+ T regulatory cells. Immunization with 4-1BBL in combination with an E7 peptide or survivin protein resulted in eradication of TC-1 and 3LL tumors, respectively. 4-1BBL was more effective than TLR agonists LPS, MPL, CpG, and an agonistic 4-1BB Ab as a component of E7 peptide-based therapeutic vaccine for the generation of immune responses and eradication of TC-1 established tumors in the absence of detectable toxicity. Therapeutic efficacy was associated with reversal of tumor mediated nonresponsiveness/anergy as well as establishment of long-term CD8+ T cell memory. Potent pleiotropic immunomodulatory activities combined with lack of toxicity highlight the potential of 4-1BBL molecule as an effective component of therapeutic cancer vaccines.