可溶性BTLA协同HSP70疫苗增强肿瘤免疫效应及其分子机制的研究
摘要
B、T淋巴细胞弱化因子(BTLA)是一种属于免疫球蛋白超家族的免疫抑制性受体，而它的配体单纯疱疹病毒进入介质(HVEM)是肿瘤坏死因子超家族的成员之一，这是目前为止发现的唯一一对来源于两个不同的超家族的成员相互作用的例子。它们的相互作用引发了一系列的问题，比如它们的结构差别这么大是如何相互作用的，相互作用后产生的下游信号是怎么样的等等。进来的许多研究表明HVEM与其内源性配体来自肿瘤坏死因子超家族的另一位成员LIGHT相互作用可以引发强大的免疫应答，而HVEM与BTLA相互作用对T细胞应答产生负性调节作用。
有研究发现，通过一定手段阻断BTLA-HVEM相互作用能够增强适应性免疫应答，有利于抑制肿瘤生长。然而，阻断此抑制性通路是否能作为治疗性手段对已经形成的肿瘤产生治疗效应还不为人知。本研究中，我们阐述了利用BTLA胞外段这种可溶性分子，去封闭HVEM上的结合位点，阻断膜型BTLA与HVEM相互作用，并协同HSP70疫苗产生强大的抗肿瘤效应，并对其分子机制进行了阐述。我们用小鼠TC-1细胞局部肌肉注射构建原位肿瘤模型，B16F10细胞尾静脉注射构建肺转移模型，用质粒psBTLA和腺相关病毒装载的sBTLA-AAV协同HSP70-TC1抗原肽和HSP70-B16抗原肽作为治疗手段，对可溶性BTLA分子的肿瘤免疫增强效应进行了系统的研究。我们通过对肿瘤局部微环境中的免疫调节基因的表达进行检测分析来阐明联合治疗的分子机制，通过分析浸润到肿瘤局部的肿瘤特异淋巴细胞的表型、数量和功能以及测量肿瘤大小、监测小鼠生存率来评估免疫治疗的效果。我们发现单独应用可溶性BTLA分子的增强肿瘤免疫作用是非常有限的，但联合应用HSP70肿瘤抗原肽后，增强肿瘤免疫的效果非常明显，治疗效应令人满意。我们分析肿瘤微环境中免疫相关调节基因的表达发现联合治疗能够显著增加Th1类细胞因子IL-2、IFN-γ的表达水平，同时保持IL-10、TGF-β和foxp3等负性调节因子的持续低水平状态，并且可以产生更强更持久的免疫记忆效应。总之，利用可溶性BTLA分子阻断BTLA-HVEM负调节通路，可以显著增强HSP70疫苗的抗肿瘤效应，是进一步促进肿瘤免疫应答从而获得显著治疗效应的有效靶点。
The interaction between B and T lymphocyte attenuator (BTLA), an inhibitory receptor whose extracellular domain belongs to the immunoglobulin superfamily, and herpesvirus-entry mediator (HVEM), a co-stimulatory tumour-necrosis factor receptor, is unique in that it is the only receptor-ligand interaction that directly bridges these two families of receptors. This interaction has raised many questions about how receptors from two different families could interact and what downstream signalling events might occur as a result of receptor ligation. As we discuss, recent studies show that engagement of HVEM with its endogenous ligand (LIGHT) from the tumour-necrosis factor family induces a powerful immune response, whereas HVEM interactions with BTLA negatively regulate T-cell responses.
Blocking BTLA-HVEM interaction augments adaptive immune response which benefits the prevention of tumor. However, whether it is effective as a therapeutic tool against established tumors is not well elucidated. In the present study, we evaluated the efficacy and mechanism of immunotherapy with soluble BTLA derived from psBTLA alone or sBTLA-AAV alone or its combination with HSP70 vaccine. The murine TC-1 cervical cancer served as an ectopic tumor model. The murine B16F10 melanoma served as a metastatic tumor model. The synergistic mechanism of combination therapy was elucidated by detecting the change of gene expression of immunoregulatory factors in tumor microenvironment. The effects of immunotherapy were evaluated by detecting the function of tumor-specific T cells, measuring tumor weight or survival of mice, and H&E staining of tissues. We found local gene transfer by injection of psBTLA alone possessed antitumor effect but limited, whereas, it significantly improve HSP70 vaccine-mediated antitumor immunity. Gene expression detection in tumor microenvironment showed significantly higher transcription activities of Th1 cytokines IL-2 and IFN-γgene and lower level of negative regulatory molecules IL-10, TGF-βand foxp3 in combination therapy group. Moreover, combination therapy could generate stronger memory effect. Taken together, our findings indicate that blocking BTLA-HVEM interaction with sBTLA enhances antitumor efficacy and showed significantly combined effect with HSP70 vaccine against the in vivo existent tumor cells.
有研究发现，通过一定手段阻断BTLA-HVEM相互作用能够增强适应性免疫应答，有利于抑制肿瘤生长。然而，阻断此抑制性通路是否能作为治疗性手段对已经形成的肿瘤产生治疗效应还不为人知。本研究中，我们阐述了利用BTLA胞外段这种可溶性分子，去封闭HVEM上的结合位点，阻断膜型BTLA与HVEM相互作用，并协同HSP70疫苗产生强大的抗肿瘤效应，并对其分子机制进行了阐述。我们用小鼠TC-1细胞局部肌肉注射构建原位肿瘤模型，B16F10细胞尾静脉注射构建肺转移模型，用质粒psBTLA和腺相关病毒装载的sBTLA-AAV协同HSP70-TC1抗原肽和HSP70-B16抗原肽作为治疗手段，对可溶性BTLA分子的肿瘤免疫增强效应进行了系统的研究。我们通过对肿瘤局部微环境中的免疫调节基因的表达进行检测分析来阐明联合治疗的分子机制，通过分析浸润到肿瘤局部的肿瘤特异淋巴细胞的表型、数量和功能以及测量肿瘤大小、监测小鼠生存率来评估免疫治疗的效果。我们发现单独应用可溶性BTLA分子的增强肿瘤免疫作用是非常有限的，但联合应用HSP70肿瘤抗原肽后，增强肿瘤免疫的效果非常明显，治疗效应令人满意。我们分析肿瘤微环境中免疫相关调节基因的表达发现联合治疗能够显著增加Th1类细胞因子IL-2、IFN-γ的表达水平，同时保持IL-10、TGF-β和foxp3等负性调节因子的持续低水平状态，并且可以产生更强更持久的免疫记忆效应。总之，利用可溶性BTLA分子阻断BTLA-HVEM负调节通路，可以显著增强HSP70疫苗的抗肿瘤效应，是进一步促进肿瘤免疫应答从而获得显著治疗效应的有效靶点。
The interaction between B and T lymphocyte attenuator (BTLA), an inhibitory receptor whose extracellular domain belongs to the immunoglobulin superfamily, and herpesvirus-entry mediator (HVEM), a co-stimulatory tumour-necrosis factor receptor, is unique in that it is the only receptor-ligand interaction that directly bridges these two families of receptors. This interaction has raised many questions about how receptors from two different families could interact and what downstream signalling events might occur as a result of receptor ligation. As we discuss, recent studies show that engagement of HVEM with its endogenous ligand (LIGHT) from the tumour-necrosis factor family induces a powerful immune response, whereas HVEM interactions with BTLA negatively regulate T-cell responses.
Blocking BTLA-HVEM interaction augments adaptive immune response which benefits the prevention of tumor. However, whether it is effective as a therapeutic tool against established tumors is not well elucidated. In the present study, we evaluated the efficacy and mechanism of immunotherapy with soluble BTLA derived from psBTLA alone or sBTLA-AAV alone or its combination with HSP70 vaccine. The murine TC-1 cervical cancer served as an ectopic tumor model. The murine B16F10 melanoma served as a metastatic tumor model. The synergistic mechanism of combination therapy was elucidated by detecting the change of gene expression of immunoregulatory factors in tumor microenvironment. The effects of immunotherapy were evaluated by detecting the function of tumor-specific T cells, measuring tumor weight or survival of mice, and H&E staining of tissues. We found local gene transfer by injection of psBTLA alone possessed antitumor effect but limited, whereas, it significantly improve HSP70 vaccine-mediated antitumor immunity. Gene expression detection in tumor microenvironment showed significantly higher transcription activities of Th1 cytokines IL-2 and IFN-γgene and lower level of negative regulatory molecules IL-10, TGF-βand foxp3 in combination therapy group. Moreover, combination therapy could generate stronger memory effect. Taken together, our findings indicate that blocking BTLA-HVEM interaction with sBTLA enhances antitumor efficacy and showed significantly combined effect with HSP70 vaccine against the in vivo existent tumor cells.
引文
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