Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity.
Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity.
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DOI：
10.1158/0008-5472.can-12-4241
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发表时间：
2013-04-15
期刊：
影响因子：
11.2
通讯作者：
Wu TC
中科院分区：
文献类型：
--
作者：
Kang TH;Mao CP;Lee SY;Chen A;Lee JH;Kim TW;Alvarez RD;Roden RB;Pardoll D;Hung CF;Wu TC
多种药物具有诱导促炎因子从垂死肿瘤细胞中表达和释放的潜力。因此，这些细胞在理论上可以通过各种确定的机制引发免疫反应，以永久根除播散性癌症。然而，在肿瘤微环境的背景下，化疗对肿瘤特异性免疫应答的影响在很大程度上是未知的。在肿瘤微环境中，化疗促进的免疫应答被免疫抑制环境拮抗，这些相反力量的平衡决定了疾病的临床过程。在这里，我们报告说，化疗后肿瘤微环境中的高抗原暴露足以使这种平衡偏向于产生有效的免疫反应。在提高抗原暴露方面，化疗可以实现长期控制肿瘤进展，而不需要额外的佐剂。我们发现，化疗通过树突状细胞的积累在肿瘤微环境中引发了这种现象，树突状细胞刺激了CD8+ T细胞和I型干扰素通路。从这个概念基础上，我们开发了一种简单的方法，结合化疗和疫苗接种，可能是广泛适用的癌症治疗。
Multiple classes of pharmacologic agents have the potential to induce the expression and release of pro-inflammatory factors from dying tumor cells. As a result, these cells can in theory elicit an immune response through various defined mechanisms to permanently eradicate disseminated cancer. However, the impact of chemotherapy on the tumor-specific immune response in the context of the tumor microenvironment is largely unknown. Within the tumor microenvironment, the immune response promoted by chemotherapy is antagonized by an immune-suppressive milieu, and the balance of these opposing forces dictates the clinical course of disease. Here we report that high antigen exposure within the tumor microenvironment following chemotherapy is sufficient to skew this balance in favor of a productive immune response. In elevating antigen exposure, chemotherapy can achieve long-term control of tumor progression without the need of an additional adjuvant. We found that chemotherapy initiated this phenomenon in the tumor microenvironment through an accumulation of dendritic cells, which stimulated CD8+ T cells and the type-I interferon pathway. From this conceptual base, we developed a simple approach to cancer therapy combining chemotherapy and vaccination that may be widely applicable.