Department of Polymer Science and Engineering, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea.
Department of Biomedical Sciences, Chonnam National University Medical School, 160 Baekseo-ro, Gwangju 58128, Republic of Korea.
ACS Appl Mater Interfaces. 2021 Feb 3;13(4):4844-4852. doi: 10.1021/acsami.0c20063. Epub 2021 Jan 24.
The combination of photothermal therapy (PTT) and toll-like receptor (TLR)-mediated immunotherapy can elicit antitumor immunity and modulate the immunosuppressive tumor microenvironment (TME). Unlike other TLRs, TLR-5 is a promising target for immune activation, as its expression is well-maintained even during immunosenescence. Here, we developed a unique tumor microenvironment-regulating immunosenescence-independent nanostimulant consisting of TLR-5 adjuvant flagellin B (FlaB) conjugated onto the surface to an IR 780-loaded hyaluronic acid-stearylamine (HIF) micelles. These HIF micelles induced immune-mediated cell death PTT when irradiated with a near-infrared laser. In comparison with PTT alone, the combination of -generated tumor-associated antigens produced during PTT and the immune adjuvant FlaB demonstrated enhanced vaccine-like properties and modulated the TME by suppressing immune-suppressive regulatory cells (Tregs) and increasing the fraction of CD103 migratory dendritic cells, which are responsible for trafficking tumor antigens to draining lymph nodes (DLNs). This combinatorial strategy (, applying a TLR-5 adjuvant targeted to immunosenescence-independent TLR-5 and the photothermal generation of tumor-associated antigens) is a robust system for next-generation immunotherapy and could even be applied in elderly patients, thus broadening the clinical scope of immunotherapy strategies.
光热疗法（PTT）与 Toll 样受体（TLR）介导的免疫疗法相结合，可以引发抗肿瘤免疫并调节免疫抑制性肿瘤微环境（TME）。与其他 TLR 不同，TLR-5 是免疫激活的有前途的靶标，因为即使在免疫衰老期间，其表达也能得到很好的维持。在这里，我们开发了一种独特的肿瘤微环境调节免疫衰老非依赖性纳米刺激剂，该刺激剂由 TLR-5 佐剂鞭毛蛋白（FlaB）与负载近红外光（IR）780 的透明质酸-硬脂胺（HIF）胶束表面连接而成。当用近红外激光照射时，这些 HIF 胶束会引发免疫介导的细胞死亡 PTT。与单独的 PTT 相比，PTT 过程中产生的肿瘤相关抗原与免疫佐剂 FlaB 的联合应用表现出增强的疫苗样特性，并通过抑制免疫抑制性调节细胞（Tregs）和增加负责将肿瘤抗原运送到引流淋巴结（DLNs）的 CD103 迁移树突状细胞的比例来调节 TME。这种组合策略（，应用靶向免疫衰老非依赖性 TLR-5 的 TLR-5 佐剂和光热产生的肿瘤相关抗原）是下一代免疫疗法的强大系统，甚至可以应用于老年患者，从而拓宽了免疫疗法策略的临床范围。
