Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Brussels, B-1200, Belgium.
Institute of Oncology Ljubljana, Department of Experimental Oncology, Zaloska 2, SI-1000, Ljubljana, Slovenia.
Sci Rep. 2018 Oct 24;8(1):15732. doi: 10.1038/s41598-018-33933-7.
DNA vaccination against cancer has become a promising strategy for inducing a specific and long-lasting antitumor immunity. However, DNA vaccines fail to generate potent immune responses when used as a single therapy. To enhance their activity into the tumor, a DNA vaccine against murine P815 mastocytoma was combined with antibodies directed against the immune checkpoints CTLA4 and PD1. The combination of these two strategies delayed tumor growth and enhanced specific antitumor immune cell infiltration in comparison to the corresponding single therapies. The combination also promoted IFNg, IL12 and granzyme B production in the tumor microenvironment and decreased the formation of liver metastasis in a very early phase of tumor development, enabling 90% survival. These results underline the complementarity of DNA vaccination and immune checkpoint blockers in inducing a potent immune response, by exploiting the generation of antigen-specific T cells by the vaccine and the ability of immune checkpoint blockers to enhance T cell activity and infiltration in the tumor. These findings suggest how and why a rational combination therapy can overcome the limits of DNA vaccination but could also allow responses to immune checkpoint blockers in a larger proportion of subjects.
DNA 疫苗接种治疗癌症已成为诱导特异性和持久性抗肿瘤免疫的一种有前途的策略。然而，当 DNA 疫苗作为单一疗法使用时，无法产生有效的免疫反应。为了增强其在肿瘤中的活性，针对小鼠 P815 肥大细胞瘤的 DNA 疫苗与针对免疫检查点 CTLA4 和 PD1 的抗体联合使用。与相应的单一疗法相比，这两种策略的联合延迟了肿瘤生长并增强了特异性抗肿瘤免疫细胞浸润。该联合还促进了肿瘤微环境中 IFNg、IL12 和 granzyme B 的产生，并在肿瘤发展的极早期阶段减少了肝转移的形成，使 90%的动物存活。这些结果强调了 DNA 疫苗接种和免疫检查点抑制剂在诱导有效免疫反应方面的互补性，通过利用疫苗产生抗原特异性 T 细胞和免疫检查点抑制剂增强 T 细胞活性和浸润肿瘤的能力。这些发现说明了合理的联合治疗如何以及为什么能够克服 DNA 疫苗接种的局限性，但也可能使更大比例的患者对免疫检查点抑制剂产生反应。
