Vasquez Marcos, Paredes-Cervantes Vladimir, Aranda Fernando, Ardaiz Nuria, Gomar Celia, Berraondo Pedro
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, Spain.
Centro Médico Nacional La Raza, IMSS, México DF, Mexico.
Oncotarget. 2017 Jan 17;8(3):5247-5255. doi: 10.18632/oncotarget.14127.
Interferon alpha (IFNα) is a cytokine approved for the treatment of several types of cancer. However, the modest effect on overall survival and the high toxicity associated with the treatment has reduced the clinical use of this cytokine. In this study, we have developed a tumor model that reproduces this clinical setting. A high dose of an adeno-associated virus encoding IFNα (AAV-IFNα) was able to eradicate a liver metastases model of colon cancer but induced lethal pancytopenia. On the other hand, a safe dose of AAV-IFNα was not able to eliminate the liver metastases of colon cancer. In this IFNα-resistant tumor model, administration of an adeno-associated vector encoding apolipoprotein A-1 fused to IFNα was able to fully eradicate the tumor in 43% of mice without toxicity. This antitumor effect was limited by suboptimal long-term CD8+ T cell activation and the expansion of T regulatory cells. In contrast, IFNα upregulated suppressor molecules such as PD-1 and interleukin 10 on CD8+ T lymphocytes. In conclusion, we show that apolipoprotein A-1 fused to IFNα is a novel antitumor drug that differs from IFNα in the modulation of suppressor mechanisms of the immune response. These differential properties pave the way for rational combinations with other immunomodulatory drugs.
干扰素α（IFNα）是一种已被批准用于治疗多种癌症的细胞因子。然而，其对总生存期的疗效有限以及与治疗相关的高毒性降低了这种细胞因子的临床应用。在本研究中，我们建立了一种重现这种临床情况的肿瘤模型。高剂量编码IFNα的腺相关病毒（AAV-IFNα）能够根除结肠癌肝转移模型，但会诱发致死性全血细胞减少。另一方面，安全剂量的AAV-IFNα无法消除结肠癌的肝转移。在这个对IFNα耐药的肿瘤模型中，给予编码与IFNα融合的载脂蛋白A-1的腺相关载体能够在43%的小鼠中完全根除肿瘤且无毒性。这种抗肿瘤作用受到长期CD8 + T细胞激活不充分和调节性T细胞扩增的限制。相比之下，IFNα会上调CD8 + T淋巴细胞上的抑制分子，如PD-1和白细胞介素10。总之，我们表明与IFNα融合的载脂蛋白A-1是一种新型抗肿瘤药物，在免疫反应抑制机制的调节方面与IFNα不同。这些不同特性为与其他免疫调节药物的合理联合应用铺平了道路。
