Enhanced antitumor responses elicited by combinatorial protein transfer of chemotactic and costimulatory molecules
Enhanced antitumor responses elicited by combinatorial protein transfer of chemotactic and costimulatory molecules
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DOI：
10.4049/jimmunol.178.5.3301
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Chen, Aoshuang
中科院分区：
文献类型：
--
作者：
Liu, Shanrong;Breiter, Deborah R.;Chen, Aoshuang
迄今为止，基于一种或几种免疫刺激分子的免疫疗法显示出有限的抗肿瘤功效。这突出了需要使用多种免疫刺激分子，以同时靶向不同的免疫细胞，包括免疫抑制细胞。因此，在本研究中，我们通过蛋白质转移的方式将四种分子，包括趋化分子次级淋巴组织趋化因子和Fas配体，以及共刺激分子4-1BBL和TNF相关的活化诱导细胞因子，经尿道递送。次级淋巴组织趋化因子和Fas配体一起可以吸引一系列免疫细胞并诱导CD 4（+）CD 25（+）调节性T细胞（Treg）凋亡，而4-IBBL和TRANCE一起可以刺激T细胞和树突状细胞（DCs）。我们表明，所有四种分子的转移都会增加肿瘤浸润中性粒细胞、DC以及CD 4（+）和CDS+ T细胞，并减少瘤内Treg。我们发现，治疗有利于在肿瘤部位产生Th 1细胞因子环境，这不仅归因于产生IL-12的DC和产生IFN-γ的CD 8（+）T细胞的增加，而且归因于产生IL-10的Treg的减少。重要的是，在L5178 Y淋巴瘤模型中，我们表明，与单独转移趋化分子或单独转移共刺激分子相比，转移所有四种分子对已建立的肿瘤表现出更强的抗肿瘤反应。此外，我们表明，所有四种分子的转移引起的抗肿瘤反应是由长期的，系统的抗肿瘤免疫介导的。因此，这项研究首次证明，组合使用趋化和共刺激分子提供了一个有用的策略，增强抗肿瘤反应。
Thus far, immunotherapies based on one or a few immunostimulatory molecules have shown limited antitumor efficacy. This highlights the need to use multiple immunostimulatory molecules, to target different immune cells, including immunosuppressive cells, simultaneously. Consequently, in this study, we delivered intraturnorally via protein transfer four molecules, including the chemotactic molecules secondary lymphoid tissue chemokine and Fas ligand and the costimulatory molecules 4-1BBL and TNFrelated activation -induced cytokine. Secondary lymphoid tissue chemokine and Fas ligand together can attract an array of immune cells and induce apoptosis in CD4(+)CD25(+) regulatory T cells (Treg), whereas 4-IBBL and TRANCE together can stimulate T cells and dendritic cells (DCs). We show that the transfer of all four molecules increases tumor-infiltrating neutrophils, DCs, and CD4(+) and CDS+ T cells and decreases intratumoral Treg. We show that the treatment favors the generation of a Th1 cytokine milieu at the tumor site, which is attributed not only to an increase in IL-12-producting DCs and IFN-gamma-producing CD8(+) T cells, but also to a decrease in IL-10-producing Treg. Importantly, in the L5178Y lymphoma model, we show that compared with transfer of the chemotactic molecules alone or the costimulatory molecules alone, transfer of all four molecules demonstrates stronger antitumor responses against established tumors. Furthermore, we show that the antitumor responses elicited by transfer of all four molecules are mediated by long-term, systemic antitumor immunity. Hence, this study demonstrates for the first time that combinatorial use of chemotactic and costimulatory molecules provides a useful strategy for enhancing antitumor responses.