One driver of the high failure rates of clinical trials for therapeutic cancer vaccines is likely the inability to sufficiently engage conventional dendritic cells (cDCs), the antigen-presenting cell (APC) subset that is specialized in priming antitumor T cells. Here, we demonstrate that, relative to vaccination with an injectable mesoporous silica rod (MPS) vaccine alone (Vax), combining MPS vaccines with CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2cx) drives ~3-fold expansion of cDCs at the vaccination sites, vaccine-draining lymph nodes, and spleens of treated mice. Furthermore, relative to Vax alone, Vax+IL-2cx led to a ~3-fold increase in the numbers of CD8 + T cells and ~15-fold increase in the numbers of NK cells at the vaccination site. Notably, with both the model protein antigen OVA as well as various peptide neoantigens, Vax+IL-2cx induced ~5 to 30-fold greater numbers of circulating antigen-specific CD8 + T cells relative to Vax alone. We further demonstrate that Vax+IL-2cx leads to significantly improved efficacy in the MC38 colon carcinoma model relative to either monotherapy alone, driving complete regressions in 50% of mice in a cDC-dependent manner. Relative to vaccine alone, Vax+IL-2cx led to comparable numbers of CD8 + T cells, but markedly greater numbers of NK cells and activated cDCs in the B16F10 melanoma tumor microenvironment post-therapy. Taken together, these findings suggest that the administration of factors that engage both the cDC-CD8 + T cell and cDC-NK cell axes can boost the potency of therapeutic cancer vaccines.

中文翻译：

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IL-2/抗 IL-2 抗体复合物增强对治疗性癌症疫苗的免疫反应


治疗性癌症疫苗临床试验失败率高的一个驱动因素可能是无法充分参与传统的树突状细胞 （cDC），即专门用于引发抗肿瘤 T 细胞的抗原呈递细胞 （APC） 亚群。在这里，我们证明，相对于单独使用可注射介孔二氧化硅棒 （MPS） 疫苗 （Vax） 进行疫苗接种，将 MPS 疫苗与 CD122 偏向的 IL-2/抗 IL-2 抗体复合物 （IL-2cx） 相结合，可驱动 cDC 在疫苗接种部位、疫苗引流淋巴结和治疗小鼠的脾脏处扩增 ~3 倍。此外，相对于单独的 Vax，Vax+IL-2cx 导致疫苗接种部位 CD8 + T 细胞的数量增加 ~3 倍，NK 细胞数量增加 ~15 倍。值得注意的是，对于模型蛋白抗原 OVA 以及各种肽新抗原，Vax+IL-2cx 诱导的循环抗原特异性 CD8 + T 细胞数量相对于单独的 Vax 多 ~5 至 30 倍。我们进一步证明，相对于单独的单一疗法，Vax + IL-2cx 导致 MC38 结肠癌模型的疗效显着提高，以 cDC 依赖性方式驱动 50% 的小鼠完全消退。相对于单独疫苗，Vax+IL-2cx 导致 CD8 + T 细胞数量相当，但治疗后 B16F10 黑色素瘤肿瘤微环境中 NK 细胞和活化 cDC 的数量明显增加。综上所述，这些发现表明，同时参与 cDC-CD8 + T 细胞和 cDC-NK 细胞轴的因子的给药可以提高治疗性癌症疫苗的效力。