PD-1 blockade enhances radio-immunotherapy efficacy in murine tumor models
PD-1 blockade enhances radio-immunotherapy efficacy in murine tumor models
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DOI：
10.1007/s00432-018-2723-4
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发表时间：
2018-08
影响因子：
3.6
通讯作者：
Zhuang Yuan;Sihan Li;Huihui Wang;J. Pi;Yuhui Xing;Guang Li
中科院分区：
文献类型：
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作者：
Zhuang Yuan;Sihan Li;Huihui Wang;J. Pi;Yuhui Xing;Guang Li
目的在癌症治疗中，免疫治疗可以提高放射治疗的效果，这一点已经越来越清楚。在本研究中，我们评估了一种由局部放疗、CpG瘤内注射和PD-1全身阻断组成的新型三联疗法在肺癌模型中的疗效。用免疫细胞和细胞因子的频率和百分比来评价这种新型三联疗法的免疫效果。结果这种三联疗法比其亚组分更有效，其积极的抗肿瘤作用包括抑制肿瘤生长和提高宿主生存。这种抗肿瘤作用不仅在直接照射的肿瘤中观察到，而且在远距离肿瘤部位也以CD8+T细胞依赖的方式观察到。CD8+T细胞表型分析显示，三联疗法增加了脾内效应记忆T细胞的百分比。此外，联合治疗可显著增加肿瘤内干扰素-γ和肿瘤坏死因子-α阳性-CD8+肿瘤浸润性淋巴细胞(TIL)和成熟激活的树突状细胞(DC)的频率，提示抗肿瘤作用可能依赖于一种DC亚群的激活，该DC亚群专用于抗原交叉反应以诱导细胞毒性淋巴细胞(CTL)。此外，三联疗法减少了免疫抑制因子，如脾和肿瘤微环境中的调节性T细胞(Tregs)，同时诱导了强大的全身抗肿瘤效应。最后，三联疗法确实耐受性良好，对血象和肺活量的影响很小。结论这些结果表明，这种三联疗法促进了局部抗肿瘤免疫反应，并产生了全身性后果。这一策略的有效性和有限的毒性吸引了临床翻译。
PurposeIt has become increasingly clear in cancer treatment that radiotherapy can be enhanced by immunotherapy. In the present study, we evaluated a novel triple combination therapy consisting of local radiotherapy, intratumoral CpG, and systemic PD-1 blockade in lung cancer models.MethodsThe efficacy of a novel triple therapy was examined by recording tumor volume and survival time. The immunologic effects of this novel triple therapy were evaluated by the frequency and percentage of immune cells and cytokines using flow cytometry.ResultsThis triple combination proved more effective than its subcomponents and its positive antitumor effects included reducing tumor growth and improving host survival. The antitumor effect was not only observed in directly irradiated tumors but also in at distant tumor sites in a CD8+T-cell-dependent fashion. Phenotypic analyses of CD8+T cells revealed that the triple combination therapy increased the percentage of effector memory T cells in the spleen. Furthermore, the combination therapy significantly increased the frequency of IFN-γ and TNF-α-positive-CD8+tumor-infiltrating lymphocytes (TIL) and mature-activated dendritic cells (DCs) within treated tumors, indicating that the antitumor effects likely depend on the activation of a DC subset specialized in antigen crosspriming to induce cytotoxic lymphocyte (CTLs). In addition, the triple therapy reduced immunosuppressive factors, like regulatory T cells (Tregs) in the spleen and tumor microenvironment while inducing the robust systemic antitumor effect. Finally, the triple treatment was, indeed, well tolerated and had a little effect on the hemogram and lung.ConclusionsThese results suggest that this triple therapy promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation.