PDF(Pubmed)
Abstract：
Targeting tumor-associated angiogenesis is currently at the forefront of renal cell carcinoma (RCC) therapy, with sunitinib and bevacizumab leading to increased survival in patients with metastatic RCC (mRCC). However, resistance often occurs shortly after initiation of therapy, suggesting that targeting the tumor-associated vascular endothelium may not be sufficient to eradicate RCC. This study reports the therapeutic efficacy of a Listeria (Lm)-based vaccine encoding an antigenic fragment of CD105 (Lm-LLO-CD105A) that targets both RCC tumor cells and the tumor-associated vasculature. Lm-LLO-CD105A treatment reduced primary tumor growth in both subcutaneous and orthotopic models of murine RCC. The vaccine conferred anti-tumor immunity and remodeled the tumor microenvironment (TME), resulting in increased infiltration of polyfunctional CD8+ and CD4+ T cells and reduced infiltration of immunosuppressive cell types within the TME. We further provide evidence that the therapeutic efficacy of Lm-LLO-CD105A is mediated by CD8+ T cells and is dependent on the robust antigenic expression of CD105 by RCC tumor cells. The result from this study demonstrates the safety and promising therapeutic efficacy of targeting RCC-associated CD105 expression with Lm-based immunotherapy.
摘要：
靶向肿瘤相关血管生成目前处于肾细胞癌（RCC）治疗的前沿，舒尼替尼和贝伐单抗可提高转移性肾癌（mRCC）患者的生存率。然而,抵抗通常在开始治疗后不久发生，提示靶向肿瘤相关血管内皮可能不足以根除RCC。该研究报告了基于李斯特菌（Lm）的疫苗的治疗功效，该疫苗编码靶向RCC肿瘤细胞和肿瘤相关脉管系统的CD105（Lm-LLO-CD105A）的抗原片段。Lm-LLO-CD105A治疗减少了鼠RCC的皮下和原位模型中的原发性肿瘤生长。该疫苗赋予了抗肿瘤免疫力并重塑了肿瘤微环境（TME），导致多功能CD8+和CD4+T细胞的浸润增加，并减少TME内免疫抑制细胞类型的浸润。我们进一步提供证据表明,Lm-LLO-CD105A的治疗功效由CD8+T细胞介导,并且依赖于RCC肿瘤细胞对CD105的稳健抗原表达。这项研究的结果证明了用基于Lm的免疫疗法靶向RCC相关CD105表达的安全性和有希望的治疗效果。
