Adenovirus vaccine therapy with CD137L promotes CD8+DCs-mediated multifunctional CD8+T cell immunity and elicits potent anti-tumor activity
Adenovirus vaccine therapy with CD137L promotes CD8+DCs-mediated multifunctional CD8+T cell immunity and elicits potent anti-tumor activity
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CD137L 腺病毒疫苗疗法可促进 CD8( ) DC 介导的多功能 CD8( ) T 细胞免疫并引发有效的抗肿瘤活性。
DOI：
10.1016/j.phrs.2021.106034
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发表时间：
2022-01-01
影响因子：
9.3
通讯作者：
Wang，Gang
中科院分区：
文献类型：
--
作者：
Ding，Jiage;Jiang，Nan;Wang，Gang
肾癌在有转移性疾病的患者中进展迅速，但治疗策略有限。在这里，我们构建了编码免疫激活剂CD137L和肿瘤抗原CAIX的重组非复制型腺病毒(Ad)疫苗，用于治疗肾癌。在皮下肿瘤模型中，与单一疫苗组相比，Ad-CD137L/CAIX疫苗组的肿瘤生长明显受到抑制。在Ad-CD137L/CAIX联合免疫小鼠中，CD11c+和CD8+CD11c+树突状细胞(DC)亚群的诱导和成熟均有促进作用。此外，Ad-CD137L/CAIX疫苗诱导了更强的肿瘤特异性多功能CD8+T细胞免疫应答，表现为CD8+T细胞的增殖和杀伤功能增强。值得注意的是，CD8+T细胞的耗尽大大削弱了Ad-CD137L/CAIX疫苗的有效保护作用，这表明CD8+T细胞对疫苗的免疫效力具有不可替代的作用。在肺转移和原位模型中，与单独使用Ad-CD137L/CAIX疫苗治疗相比，Ad-CD137L/CAIX疫苗治疗显著减少了肿瘤的转移和进展，并增加了肿瘤特异性多功能CD8+T细胞的诱导。在原位和转移模型中，Ad-CD137L/CAIX疫苗还增强了肿瘤特异性多功能CD8+T细胞免疫反应。这些结果表明，Ad-CD137L/CAIX疫苗通过诱导CD8+DC介导的多功能CD8+T细胞免疫应答而产生强大的抗肿瘤活性。以CD137L为基础的疫苗可能成为治疗肾癌或其他恶性肿瘤的新策略。
Renal carcinoma progresses aggressively in patients with metastatic disease while curative strategies are limited. Here, we constructed a recombinant non-replicating adenovirus (Ad) vaccine encoding an immune activator, CD137L, and a tumor antigen, CAIX, for treating renal carcinoma. In a subcutaneous tumor model, tumor growth was significantly suppressed in the Ad-CD137L/CAIX vaccine group compared with the single vaccine group. The induction and maturity of CD11C+and CD8+CD11C+dendritic cell (DC) subsets were promoted in Ad-CD137L/CAIX co-immunized mice. Furthermore, the Ad-CD137L/CAIX vaccine elicited stronger tumor-specific multifunctional CD8+T cell immune responses as demonstrated by increased proliferation and cytolytic function of CD8+T cells. Notably, depletion of CD8+T cells greatly compromised the effective protection provided by Ad-CD137L/CAIX vaccine, suggesting an irreplaceable role of CD8+T cells for the immunopotency of the vaccine. In both lung metastatic and orthotopic models, Ad-CD137L/CAIX vaccine treatment significantly decreased tumor metastasis and progression and increased the induction of tumor-specific multifunctional CD8+T cells, in contrast to treatment with the Ad-CAIX vaccine alone. The Ad-CD137L/CAIX vaccine also augmented the tumor-specific multifunctional CD8+T cell immune response in both orthotopic and metastatic models. These results indicated that Ad-CD137L/CAIX vaccine elicited a potent anti-tumor activity by inducing CD8+DC-mediated multifunctional CD8+T cell immune responses. The potential strategy of CD137L-based vaccine might be served as a novel treatment for renal carcinoma or other malignant tumors.