Comparative analysis of cancer vaccine settings for the selection of an effective protocol in mice.
Comparative analysis of cancer vaccine settings for the selection of an effective protocol in mice.
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DOI：
10.1186/1479-5876-11-120
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发表时间：
2013-05-12
影响因子：
7.4
通讯作者：
Filaci G
中科院分区：
文献类型：
--
作者：
Kalli F;Machiorlatti R;Battaglia F;Parodi A;Conteduca G;Ferrera F;Proietti M;Tardito S;Sanguineti M;Millo E;Fenoglio D;De Palma R;Inghirami G;Filaci G
癌症疫苗被认为是一种很有前途的治疗方法。然而，他们的临床效果尚不令人满意。这可能是由于选择有效的肿瘤相关抗原(TAA)和免疫方案的困难。事实上，许多TAA的弱抗原性损害了健壮程序的设计，因此必须进行系统分析以确定最有效的TAA。在这里，我们进行了一项研究，比较不同的gp100疫苗接种策略，以确定最佳策略，以可重复的方式提供对实验性黑色素瘤的100%保护。C57BL/6J小鼠皮下接种B16F10黑色素瘤细胞，接种小鼠或人gp10025-33肽+CpG佐剂，b)鼠或人gp100基因，c)鼠或人gp10025-33肽冲击的树突状细胞(DC)。或者，在肿瘤攻击部位皮下注射中和抗IL-10单抗(MAb)以对抗调节细胞。最后，联合应用人gp10025-33多肽冲击DC疫苗和抗IL-10单抗进行联合治疗。用人gp10025-33多肽冲击的DC接种是最有效的免疫方案，尽管不能达到完全保护。给予抗IL-10单抗也显示了显著的保护作用，在另一种肿瘤-间变性大细胞淋巴瘤的小鼠身上复制了这一效果。当gp10025-33多肽致敏的DC与IL-10联合免疫时，始终达到100%的保护效果。对T细胞肿瘤浸润物的分析表明，无论是gp10025-33多肽冲击的DC疫苗还是抗IL-10单抗治疗的小鼠，CD4+颗粒酶+T细胞增加，而CD4+CD25+Foxp3+Treg细胞减少。这些数据表明，肿瘤内效应T细胞亚群和调节性T细胞亚群之间的再平衡过程可能在免疫治疗方案中发挥关键的保护作用。在这里，我们证明，在癌症疫苗战略的设置中，对不同个性化方法的比较分析可能有利于公布最有效的方案。此外，我们的发现表明，IL-10活性的抵消可能是逆转促进Treg极化的肿瘤内环境的关键，从而增加针对选定TAA的疫苗接种的效果。
Cancer vaccines are considered a promising therapeutic approach. However, their clinical results are not yet satisfactory. This may be due to the the difficulty of selection of an efficient tumor associated antigen (TAA) and immunization protocol. Indeed, the weak antigenicity of many TAA impairs the design of robust procedures, therefore a systematic analysis to identify the most efficient TAA is mandatory. Here, we performed a study to compare different gp100 vaccination strategies to identify the best strategy to provide a 100% protection against experimental melanoma in a reproducible manner. C57BL/6J mice were challenged subcutaneously with B16F10 melanoma cells, after vaccination with: a) mouse or human gp10025-33 peptide plus CpG adjuvant; b) mouse or human gp100 gene; c) mouse or human gp10025-33 peptide-pulsed dendritic cells (DC). Alternatively, a neutralizing anti-IL-10 monoclonal antibody (mAb) was subcutaneously administered at the site of tumor challenge to counteract regulatory cells. Finally, combinatorial treatment was performed associating human gp10025-33 peptide-pulsed DC vaccination with administration of the anti-IL-10 mAb. Vaccination with human gp10025-33 peptide-pulsed DC was the most effective immunization protocol, although not achieving a full protection. Administration of the anti-IL-10 mAb showed also a remarkable protective effect, replicated in mice challenged with a different tumor, Anaplastic Large Cell Lymphoma. When immunization with gp10025-33 peptide-pulsed DC was associated with IL-10 counteraction, a 100% protective effect was consistently achieved. The analysis on the T-cell tumor infiltrates showed an increase of CD4+granzyme+ T-cells and a decreased number of CD4+CD25+Foxp3+ Treg elements from mice treated with either gp10025-33 peptide-pulsed DC vaccination or anti-IL-10 mAb administration. These data suggest that processes of intratumoral re-balance between effector and regulatory T cell subpopulations may play a critical protective role in immunotherapy protocols. Here we demonstrate that, in the setting of a cancer vaccine strategy, a comparative analysis of different personalized approaches may favour the unveiling of the most effective protocol. Moreover, our findings suggest that counteraction of IL-10 activity may be critical to revert the intratumoral environment promoting Treg polarization, thus increasing the effects of a vaccination against selected TAA.
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影响因子：
8.8
作者：
Kruger-Krasagakes, S;Krasagakis, K;Garbe, C;Schmitt, E;Huls, C;Blankenstein, T;Diamantstein, T
通讯作者：
Diamantstein, T
影响因子：
5
作者：
Borghaei, Hossein;Smith, Mitchell R.;Campbell, Kerry S.
通讯作者：
Campbell, Kerry S.
影响因子：
158.5
作者：
Kantoff, Philip W.;Higano, Celestia S.;Young, J.
通讯作者：
Young, J.
影响因子：
4.4
作者：
Filaci, Gilberto;Fenoglio, Daniela;Indiveri, Francesco
通讯作者：
Indiveri, Francesco
影响因子：
7.2
作者：
Hoos A;Britten C
通讯作者：
Britten C