Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus
Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus
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DOI：
10.1158/0008-5472.can-11-2975
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发表时间：
2012-05-01
期刊：
影响因子：
11.2
通讯作者：
Hemminki, Akseli
中科院分区：
文献类型：
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作者：
Diaconu, Iulia;Cerullo, Vincenzo;Hemminki, Akseli
溶瘤腺病毒是用于免疫治疗的有吸引力的平台，因为病毒复制是高度免疫原性的并且不受耐受性的影响。虽然溶瘤释放肿瘤表位并提供共刺激危险信号，但用免疫刺激分子武装病毒可以进一步提高疗效。CD 40配体（CD 40 L，CD 154）诱导肿瘤细胞凋亡并触发几种免疫机制，包括T辅助细胞1型（T（H）1）应答，其导致细胞毒性T细胞活化和免疫抑制减少。在这项研究中，我们构建了一种新的溶瘤腺病毒，Ad 5/3-hTERT-E1 A-hCD 40 L，其特征在于嵌合的Ad 5/3衣壳增强肿瘤转导，人端粒酶逆转录酶（hTERT）启动子肿瘤选择性，和人CD 40 L增加疗效。Ad 5/3-hTERT-E1 A-hCD 40 L通过溶瘤和凋亡作用显著抑制体内肿瘤生长，并且（Ad 5/3-hTERT-E1 A-hCD 40 L）介导的溶瘤导致钙网蛋白暴露以及HMGB 1和ATP释放增加，这提示免疫原性。在两个同系小鼠模型中，鼠CD 40 L诱导抗原呈递细胞的募集和活化，导致脾细胞中白细胞介素-12的产生增加。这种效应与T（H）1细胞因子IFN-γ、RANTES和TNF-α的诱导有关。用Ad 5/3-CMV-mCD 40 L处理的肿瘤也显示出巨噬细胞和细胞毒性CD 8（+）T细胞的存在增强，但B细胞不存在。总之，我们的研究结果表明，编码CD 40 L的腺病毒介导多种抗肿瘤作用，包括溶瘤、凋亡、诱导T细胞应答和上调T（H）1细胞因子。Cancer Res; 72（9）; 2327-38. (C)2012年AACR。
Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (T(H)1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)-mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the T(H)1 cytokines IFN-gamma, RANTES, and TNF-alpha. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8(+) T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of T(H)1 cytokines. Cancer Res; 72(9); 2327-38. (C) 2012 AACR.