4-1BB ligand as an effective multifunctional immunomodulator and antigen delivery vehicle for the development of therapeutic cancer vaccines.
4-1BB ligand as an effective multifunctional immunomodulator and antigen delivery vehicle for the development of therapeutic cancer vaccines.
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DOI：
10.1158/0008-5472.can-09-4480
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发表时间：
2010-05-15
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;Schabowsky RH;Srivastava AK;Elpek KG;Madireddi S;Zhao H;Zhong Z;Miller RW;Macleod KJ;Yolcu ES;Shirwan H
基于肿瘤相关抗原（TAAs）的治疗性亚单位疫苗是治疗癌症的一种有吸引力的方法。然而，TAAs较差的免疫原性需要强效佐剂才能达到治疗效果。我们最近提出TNF家族共刺激配体作为治疗性疫苗的潜在佐剂，因此产生了一种可溶性形式的4-1BBL与链亲和素（SA-4-1BBL）嵌合物，对先天、适应性和调节性免疫细胞具有多效性作用。我们在此测试了SA-4-1BBL是否可以转化为有效的癌症免疫治疗，当SA-4-1BBL也被用作载体，在体内将TAAs传递给表达4-1BB受体的dc时。SA-4-1BBL在受体结合后被dc内化，与SA-4-1BBL结合的生物素化抗原免疫可增加dc对抗原的摄取和交叉呈递，从而产生有效的T细胞免疫应答。含有人乳头瘤病毒16 (HPV-16) E7癌蛋白或survivin作为自身TAA的结合疫苗分别对TC-1型宫颈癌和3LL型肺癌具有较强的治疗效果。疫苗的治疗效果与增加的CD4+ T和CD8+ T细胞效应和记忆反应以及更高的肿瘤内CD8+ T效应/CD4+CD25+Foxp3+ T调节细胞比率相关。因此，SA-4-1BBL强大的多效性免疫功能，加上其作为载体增加抗原在体内向dc的递送的能力，使该分子有可能作为抗癌和慢性感染治疗性疫苗的有效免疫调节成分。
Therapeutic subunit vaccines based on tumor-associated antigens (TAAs) represent an attractive approach for the treatment of cancer. However, poor immunogenicity of TAAs requires potent adjuvants for therapeutic efficacy. We recently proposed the TNF family costimulatory ligands as potential adjuvants for therapeutic vaccines, and hence generated a soluble form of 4-1BBL chimeric with streptavidin (SA-4-1BBL) that has pleiotropic effects on cells of innate, adaptive, and regulatory immunity. We herein tested whether these effects can translate into effective cancer immunotherapy when SA-4-1BBL was also used as a vehicle to deliver TAAs in vivo to DCs constitutively expressing the 4-1BB receptor. SA-4-1BBL was internalized by DCs upon receptor binding, and immunization with biotinylated antigens conjugated to SA-4-1BBL resulted in increased antigen uptake and cross-presentation by DCs, leading to the generation of effective T cell immune responses. Conjugate vaccines containing human papilloma virus 16 (HPV-16) E7 oncoprotein or survivin as a self TAA had potent therapeutic efficacy against TC-1 cervical and 3LL lung carcinoma tumors, respectively. Therapeutic efficacy of the vaccines was associated with increased CD4+ T and CD8+ T cell effector and memory responses and higher intratumoral CD8+ T effector/CD4+CD25+Foxp3+ T regulatory cell ratio. Thus, potent pleiotropic immune functions of SA-4-1BBL combined with its ability to serve as a vehicle to increase delivery of antigens to DCs in vivo endow this molecule with the potential to serve as an effective immunomodulatory component of therapeutic vaccines against cancer and chronic infections.