Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; University of Ljubljana, Biotechnical Faculty, Jamnikarjeva ulica 101, SI-1000 Ljubljana, Slovenia.
Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; University of Ljubljana, Biotechnical Faculty, Jamnikarjeva ulica 101, SI-1000 Ljubljana, Slovenia.
Bioelectrochemistry. 2021 Aug;140:107831. doi: 10.1016/j.bioelechem.2021.107831. Epub 2021 Apr 28.
In situ vaccination is a promising immunotherapeutic approach, where various local ablative therapies are used to induce an immune response against tumor antigens that are released from the therapy-killed tumor cells. We recently proposed using intratumoral gene electrotransfer for concomitant transfection of a cytotoxic cytokine tumor necrosis factor-α (TNFα) to induce in situ vaccination, and an immunostimulatory cytokine interleukin 12 (IL-12) to boost the primed immune response. Here, our aim was to test the local and systemic effectiveness of the approach in tree syngeneic mouse tumor models and associate it with tumor immune profiles, characterized by tumor mutational burden, immune infiltration and expression of PD-L1 and MHC-I on tumor cells. While none of the tested characteristic proved predictive for local effectiveness, high tumor mutational burden, immune infiltration and MHC-I expression were associated with higher abscopal effectiveness. Hence, we have confirmed that both the abundance and presentation of tumor antigens as well as the absence of immunosuppressive mechanisms are important for effective in situ vaccination. These findings provide important indications for future development of in situ vaccination based treatments, and for the selection of tumor types that will most likely benefit from it.
原位疫苗接种是一种很有前途的免疫治疗方法，各种局部消融疗法被用于诱导针对肿瘤抗原的免疫反应，这些抗原是由治疗杀死的肿瘤细胞释放的。我们最近提出使用肿瘤内基因电转移同时转染细胞毒性细胞因子肿瘤坏死因子-α（TNFα）以诱导原位疫苗接种，并转染免疫刺激性细胞因子白细胞介素 12（IL-12）以增强初始免疫反应。在这里，我们的目的是在树突状同源小鼠肿瘤模型中测试该方法的局部和全身效果，并将其与肿瘤免疫特征相关联，这些特征包括肿瘤突变负担、免疫浸润以及肿瘤细胞上 PD-L1 和 MHC-I 的表达。虽然测试的特征均不能预测局部效果，但高肿瘤突变负担、免疫浸润和 MHC-I 表达与更高的远隔效应相关。因此，我们已经证实，肿瘤抗原的丰度和呈递以及免疫抑制机制的缺失对于有效的原位疫苗接种是重要的。这些发现为基于原位疫苗接种的治疗方法的未来发展以及最有可能从中受益的肿瘤类型的选择提供了重要的依据。
