肿瘤细胞治疗研究
英文原题：Oncolytic adenovirus co-expressing IL-12 and shVEGF potentiates immune checkpoint blockade for treatment of renal cell carcinoma: in vitro, organ-on-a-chip, and in vivo evaluation.
Oncolytic adenovirus co-expressing IL-12 and shVEGF potentiates immune checkpoint blockade for treatment of renal cell carcinoma: in vitro, organ-on-a-chip, and in vivo evaluation.
肾细胞癌（RCC）因其免疫抑制性肿瘤微环境和异常的 VEGF 介导的血管生成，一直被认为是高度恶性且对标准治疗耐药的。
肾细胞癌（RCC）具有免疫抑制性肿瘤微环境及异常VEGF介导的血管生成，因此恶性程度高且对标准治疗耐药。为克服这些治疗局限，我们评估了一种共表达白细胞介素12（IL-12）和针对VEGF的短发夹RNA（shVEGF）的溶瘤腺病毒（oAd）联合免疫检查点抑制剂（ICI）的治疗效果。oAd/IL12/shVEGF可在体外及三维生物打印模型中诱导RCC特异性癌细胞死亡，抗肿瘤作用强于oAd-GMCSF；此外，该方案在RCC原位肿瘤模型中增强了抗肿瘤疗效。oAd/IL12/shVEGF联合抗PD-1所产生的强效抗肿瘤作用，归因于CD4+或CD8+ T细胞及NK细胞介导的抗肿瘤免疫反应，以及对肿瘤相关新生血管的有效抑制。总体而言，oAd/IL12/shVEGF可能是一种有力策略，可通过将免疫冷肿瘤微环境转化为炎症活化状态，使难治性肿瘤对ICI敏感，从而克服传统RCC治疗的现有限制。
Renal cell carcinoma (RCC) has been known as highly malignant and resistant to standard therapy due to its immunosuppressive tumor microenvironment and aberrant VEGF-mediated angiogenesis. To overcome these therapeutic limitations, here we assessed the therapeutic efficacy of an oncolytic adenovirus (oAd) co-expressing Interleukin-12 (IL-12) and a short hairpin RNA against VEGF (shVEGF) in combination with immune checkpoint inhibitors (ICIs). The oAd/IL12/shVEGF induced RCC-specific cancer cell death in vitro and 3D bioprinted model, leading to greater anti-tumor effect compared with oAd-GMCSF. Furthermore, it potentiates anti-tumor efficacy in RCC orthotopic tumor model. The potent antitumor effect induced by combination of oAd/IL12/shVEGF with anti-PD1 was due to CD4 + or CD8 + T cell- or NK cell-mediated antitumor immune response and effective inhibition of tumor-associated neovascularization. Collectively, oAd/IL12/shVEGF can be a potent strategy to overcome current limitations in conventional RCC therapy by converting the cold tumor microenvironment to an inflamed state to sensitize refractory tumors to ICIs.
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