Tumor Microenvironment-Regulating Immunosenescence-Independent Nanostimulant Synergizing with Near-Infrared Light Irradiation for Antitumor Immunity,ACS Applied Materials & Interfaces

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Tumor Microenvironment-Regulating Immunosenescence-Independent Nanostimulant Synergizing with Near-Infrared Light Irradiation for Antitumor Immunity
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2021-01-24 , DOI: 10.1021/acsami.0c20063
Saji Uthaman ₁ , Shameer Pillarisetti ₂ , Hye Suk Hwang ₃ , Ansuja Pulickal Mathew ₂ , Kang Moo Huh ₁ , Joon Haeng Rhee _{3,

4} , In-Kyu Park _{2,

4,

5}

Affiliation

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 Vibrio vulnificus 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 via PTT when irradiated with a near-infrared laser. In comparison with PTT alone, the combination of in situ-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 (i.e., applying a TLR-5 adjuvant targeted to immunosenescence-independent TLR-5 and the in situ 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.

中文翻译：

肿瘤微环境调节免疫衰老独立纳米刺激剂与近红外光照射协同抗肿瘤免疫

光热疗法（PTT）和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的肿瘤微环境（TME）。与其他 TLR 不同，TLR-5 是免疫激活的一个有前途的靶标，因为即使在免疫衰老过程中它的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独立纳米刺激剂，由 TLR-5 佐剂创伤弧菌鞭毛蛋白 B (FlaB) 与负载 IR 780 的透明质酸硬脂胺 (HIF) 胶束缀合组成。当用近红外激光照射时，这些 HIF 胶束通过PTT 诱导免疫介导的细胞死亡。与单独的 PTT 相比，PTT 过程中产生的原位肿瘤相关抗原与免疫佐剂 FlaB 的组合显示出增强的疫苗样特性，并通过抑制免疫抑制调节细胞 (Treg) 和增加免疫佐剂的比例来调节 TME。 CD103 ⁺迁移树突状细胞，负责将肿瘤抗原运输至引流淋巴结 (DLN)。这种组合策略（即应用针对免疫衰老无关的 TLR-5 的 TLR-5 佐剂和肿瘤相关抗原的原位光热生成）是下一代免疫治疗的强大系统，甚至可以应用于老年患者，从而拓宽了免疫治疗策略的临床范围。

更新日期：2021-02-03

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