Du Yanlin, Zhang Da, Wang Yiru, Wu Ming, Zhang Cuilin, Zheng Youshi, Zheng Aixian, Liu Xiaolong
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China.
College of Biological Science and Engineering, Fuzhou University, Fuzhou 350116, P. R. China.
Biomater Sci. 2021 Jun 4;9(11):4159-4168. doi: 10.1039/d0bm02210a.
T-lymphocytes play a potent role in cancer immunotherapy; while, limited tumor infiltrating lymphocytes (TILs) combined with severe immunosuppression always significantly hinder their antitumor immune responses, especially in solid tumors such as hepatocellular carcinoma (HCC). Here, we prepared a highly stable multifunctional aptamer for strengthening antitumor immunity against HCC solid tumors through a dual immune checkpoint blockade of CTLA-4 and PD-L1. The engineered multifunctional aptamer (termed P1/C4-bi-apt) can block both CTLA-4/B7 and PD-1/PD-L1 signaling pathways and thus enhance the antitumor immune responses. Furthermore, it can direct CTLA-4-positive T cells to infiltrate into tumors to further enhance the antitumor efficacy compared to a single blockage of CTLA-4 or PD-L1. As a result, the multifunctional aptamer can significantly inhibit tumor growth and thus improve the long-term survival of HCC-bearing mice. The designed multifunctional aptamer is simple, stable and easy to prepare, and it can significantly strengthen the functionality of T cells, holding great potential for HCC immunotherapy.
T淋巴细胞在癌症免疫治疗中发挥着重要作用；然而，有限的肿瘤浸润淋巴细胞（TILs）与严重的免疫抑制相结合，总是会显著阻碍其抗肿瘤免疫反应，尤其是在肝细胞癌（HCC）等实体瘤中。在此，我们制备了一种高度稳定的多功能适体，通过对CTLA-4和PD-L1进行双重免疫检查点阻断，增强针对HCC实体瘤的抗肿瘤免疫力。工程化的多功能适体（称为P1/C4-双适体）可以阻断CTLA-4/B7和PD-1/PD-L1信号通路，从而增强抗肿瘤免疫反应。此外，与单一阻断CTLA-4或PD-L1相比，它可以引导CTLA-4阳性T细胞浸润到肿瘤中，进一步提高抗肿瘤疗效。因此，多功能适体可以显著抑制肿瘤生长，从而提高荷HCC小鼠的长期生存率。所设计的多功能适体简单、稳定且易于制备，它可以显著增强T细胞的功能，在HCC免疫治疗中具有巨大潜力。
