Systemic blockade of transforming growth factor-beta signaling augments the efficacy of immunogene therapy.
Systemic blockade of transforming growth factor-beta signaling augments the efficacy of immunogene therapy.
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DOI：
10.1158/0008-5472.can-08-1494
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发表时间：
2008-12-15
期刊：
影响因子：
11.2
通讯作者：
Albelda SM
中科院分区：
文献类型：
--
作者：
Kim S;Buchlis G;Fridlender ZG;Sun J;Kapoor V;Cheng G;Haas A;Cheung HK;Zhang X;Corbley M;Kaiser LR;Ling L;Albelda SM
局部产生的TGF-β促进肿瘤诱导的免疫抑制，并有助于抵抗免疫治疗。本文探讨了使用TGF-β I型受体激酶抑制剂SM 16将免疫疗法与TGF-β抑制相结合时提高疗效的潜力。将表达IFNβ的腺病毒（Ad.IFNβ）在已建立的皮下AB 12（间皮瘤）和LKR（肺癌）肿瘤中瘤内注射一次，或在K-ras原位肺肿瘤模型中瘤内注射一次。用两次注射表达HPV-E7的腺病毒（Ad.E7）接种携带TC 1（肺癌）肿瘤的小鼠。SM 16在配制的食物中经口给药。通过真实的时间-PCR和流式细胞术评估肿瘤生长并测量肿瘤和脾脏中的精氨酸表达和细胞群体。SM 16增强了两种免疫疗法在每个模型中的功效，并引起肿瘤微环境的变化。SM 16和Ad.INFβ联合使用增加了肿瘤内白细胞（包括巨噬细胞、NK细胞和CD 8+细胞）的数量，并增加了表达活化标志物CD 25的T细胞的百分比。SM 16还增强了Ad.E7在TC 1侧腹肿瘤模型中的抗肿瘤作用。该组合并没有增加脾脏中HPV-E7四聚体阳性CD 8 + T细胞，但确实诱导了肿瘤的显著增加。SM 16处理小鼠的肿瘤显示免疫刺激性细胞因子和趋化因子以及内皮粘附分子的mRNA和蛋白质增加，表明肿瘤内白细胞运输增加的机制。阻断TGF-β信号通路可增强Ad.INFβ免疫激活或Ad.E7疫苗接种治疗的抗肿瘤作用。在免疫疗法的临床试验中加入TGF-β阻断剂可提高疗效。
Locally-produced TGF-β promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This paper explores the potential for increased efficacy when combining immunotherapies with TGF-β suppression using the TGF-β type I receptor kinase inhibitor, SM16. Adenovirus expressing IFNβ (Ad.IFNβ) was injected intratumorally once in established subcutaneous AB12 (mesothelioma) and LKR (lung cancer) tumors or intratracheally in a K-ras orthotopic lung tumor model. Mice bearing TC1 (lung cancer) tumors were vaccinated with two injections of adenovirus expressing HPV-E7 (Ad.E7). SM16 was administered orally in formulated chow. Tumor growth was assessed and cytokine-expression and cell populations were measured in tumors and spleens by real time-PCR and flow cytometry. SM16 potentiated the efficacy of both immunotherapies in each of the models and caused changes in the tumor microenvironment. The combination of SM16 and Ad.INFβ increased the number of intratumoral leukocytes (including macrophages, NK cells, and CD8+ cells) and increased the percentage of T-cells expressing the activation marker CD25. SM16 also augmented the anti-tumor effects of Ad.E7 in the TC1 flank tumor model. The combination did not increase HPV-E7 tetramer-positive CD8+ T cells in the spleens, but did induce a marked increase in the tumors. Tumors from SM16-treated mice showed increased mRNA and protein for immunostimulatory cytokines and chemokines, as well as endothelial adhesion molecules, suggesting a mechanism for the increased intratumoral leukocyte trafficking. Blockade of the TGF-β signaling pathway augments the anti-tumor effects of Ad.INFβ immune-activating or Ad.E7 vaccination therapy. The addition of TGF-β blocking agents in clinical trials of immunotherapies may increase efficacy.