Reactivation of type I interferon pathway to increase the efficacy of chemotherapy

摘要 I型干扰素（IFN 1，包括IFNα和IFNβ）是肠上皮细胞的关键调节因子 细胞增殖和抗肿瘤免疫应答。因此，药理学IFN 1是 用于单独或与5-氟尿嘧啶（5 FU）联合治疗结直肠癌（CRC）- 基础化疗。然而，这些方法产生了令人印象深刻的结果，表明， 介导IFN 1作用的内源性途径在CRC中不知何故失活。重要的是所有 内源性或药理学IFN 1的作用需要IFNAR 1受体链， 对于抗癌治疗方案的疗效至关重要，包括放射性和 化疗有趣的是，我们最近发现，IFN 1-IFNAR 1确实是失活的， 《儿童权利公约》。我们最近发表的数据表明，（a）IFNAR 1经历泛素化， 响应于肿瘤微环境因子如肿瘤衍生的囊泡而快速降解， (b)IFNAR 1通常在人CRC的恶性和良性肿瘤细胞中下调，和（c） 低水平的IFNAR 1与接受标准治疗的CRC患者的生存率低相关 化疗然后，我们的额外试点实验集中在克服 IFNAR 1的损失，以恢复化疗的疗效。这些实验的数据显示， 有希望使用几种方法重新激活IFN 1-IFNAR 1途径。这些包括 新的和令人兴奋的小分子sumoylation抑制剂TAK 981，以及利血平， 预防肿瘤源性囊泡作用的消肿药物。此外，令人兴奋的结果是 使用新的和独特的突变重组IFN 1（sIFN-I）获得，所述突变重组IFN 1（sIFN-I）表现出增加的 它对IFNAR 1具有亲和力，甚至在低IFNAR 1密度下也能起作用。这些最近发布和试点的 数据提供了一个有力的支持的一个总体假设，即在CRC中IFNAR 1的损失 破坏了它的治疗，相反，IFN 1途径的重新激活将增加 CRC化疗的疗效。为了检验这一假设，我们建议（i）确定 IFNAR 1缺失在大肠腺癌对含5-FU化疗反应中的重要性 方案（FOLFOX），有或没有新的sIFN-I;（ii）使用新的IFN-1-IFNAR 1途径重新激活IFN 1-IFNAR 1途径。 新的类小泛素化抑制剂TAK 981，以增加化疗的功效;和（iii）预防 通过干扰肿瘤衍生囊泡的作用，使用利血平， 提高FOLFOX的疗效。这些研究的完成应该揭示了一个新的作用， IFNAR 1的失活在CRC治疗的次优功效中，并克服该问题 通过使用重新激活IFN 1-IFNAR 1通路的方法。

ABSTRACT Type I interferons (IFN1, including IFNα and IFNβ) are critical regulators of intestinal epithelial cells proliferation and of anti-tumor immune responses. Accordingly, pharmacologic IFN1 were used in treatment of colorectal cancer (CRC) alone or combined with the 5-fluorouracil (5FU)- based chemotherapy. However, these approaches yielded underwhelming results indicating that the endogenous pathway mediating IFN1 effects is somehow inactivated in CRC. Importantly, all effects of endogenous or pharmacologic IFN1 require the IFNAR1 receptor chain, which is also essential for the efficacy of the anti-cancer treatment regimens including radio- and chemotherapies. Intriguingly, we recently found that the IFN1-IFNAR1 is indeed inactivated in CRC. Our recently published data demonstrate that (a) IFNAR1 undergoes ubiquitination and rapid degradation in response to tumor microenvironment factors such as tumor-derived vesicles, (b) IFNAR1 is often downregulated in malignant and benign tumor cells in human CRC, and (c) low levels of IFNAR1 correlates with poor survival of CRC patients who received standard chemotherapies. Our additional pilot experiments were then focused on ability to overcome the loss of IFNAR1 to restore the efficacy of chemotherapy. Data from these experiments showed a promise for reactivation of the IFN1-IFNAR1 pathway using several approaches. These include a novel and exciting small molecule sumoylation inhibitor TAK981, as well as reserpine, a hypotensive drug preventing the effects of tumor-derived vesicles. In addition, exciting results are obtained using a novel and unique mutant recombinant IFN1 (sIFN-I) that exhibits an increased affinity to IFNAR1 and can act even at low IFNAR1 density. These recently published and pilot data provide a firm support for an overarching hypothesis that the loss of IFNAR1 in CRC undermines its treatment and, conversely, reactivation of the IFN1 pathway will increase the efficacy of CRC chemotherapy. To test this hypothesis, we propose to (i) determine the importance of IFNAR1 loss in responses of colorectal adenocarcinomas to 5-FU-containing regimen (FOLFOX) with or without novel sIFN-I; (ii) reactivate the IFN1-IFNAR1 pathway using a novel sumoylation inhibitor TAK981 to increase the efficacy of chemotherapy; and (iii) prevent the loss of IFNAR1 by interfering with the effect of tumor-derived vesicles using reserpine to increase the efficacy of FOLFOX. Completion of these studies should reveal a novel role of inactivation of IFNAR1 in the sub-optimal efficacy of CRC therapy and to overcome this problem through using the means to reactivate the IFN1-IFNAR1 pathway.