Chen Po-Ming, Pan Wen-Yu, Wu Cheng-Yu, Yeh Ching-Yen, Korupalli Chiranjeevi, Luo Po-Kai, Chou Chun-Ju, Chia Wei-Tso, Sung Hsing-Wen
Department of Chemical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Department of Orthopedics, National Taiwan University Hospital, Hsinchu Branch, Hsinchu, Taiwan, ROC.
Biomaterials. 2020 Feb;230:119629. doi: 10.1016/j.biomaterials.2019.119629. Epub 2019 Nov 15.
Most cancer vaccines under development are associated with defined tumor antigens rather than with all antigens of whole tumor cells, limiting the anti-tumor immune responses that they elicit. This work proposes an immunomodulator (R848)-loaded nanoparticle system (R848@NPs) that can absorb near-infrared light (+NIR) to cause low-temperature hyperthermia that interacts synergistically with its loaded R848 to relieve the tumor-mediated immunosuppressive microenvironment, generating robust anti-tumor memory immunity. In vitro results reveal that the R848@NPs could be effectively internalized by dendritic cells, causing their maturation and the subsequent regulation of their anti-tumor immune responses. Post-treatment observations in mice in which tumors were heat-treated at high temperatures reveal that tumor growth was significantly inhibited initially but not in the longer term, while low-temperature hyperthermia or immunotherapy alone simply delayed tumor growth. In contrast, a combined therapy that involved low-temperature hyperthermia and immunotherapy using R848@NPs/+NIR induced a long-lasting immunologic memory and consequently inhibited tumor growth and prevented cancer recurrence and metastasis. These results suggest that the method that is proposed herein is promising for generating cancer vaccines in situ, by using the tumor itself as the antigen source and the introduced R848@NPs/+NIR to generate a long-term anti-tumor immunity, for personalized immunotherapy.
大多数正在研发的癌症疫苗与特定的肿瘤抗原相关联，而非与整个肿瘤细胞的所有抗原相关联，这限制了它们引发的抗肿瘤免疫反应。这项研究提出了一种负载免疫调节剂（R848）的纳米颗粒系统（R848@NPs），该系统可以吸收近红外光（+NIR）以引起低温热疗，其与负载的R848协同作用，以缓解肿瘤介导的免疫抑制微环境，产生强大的抗肿瘤记忆免疫。体外实验结果表明，R848@NPs可被树突状细胞有效内化，使其成熟并随后调节其抗肿瘤免疫反应。对高温热疗肿瘤的小鼠进行的治疗后观察表明，肿瘤生长最初受到显著抑制，但长期来看并非如此，而单独的低温热疗或免疫疗法只是延缓了肿瘤生长。相比之下，一种结合了低温热疗和使用R848@NPs/+NIR进行免疫治疗的联合疗法诱导了持久的免疫记忆，从而抑制了肿瘤生长并预防了癌症复发和转移。这些结果表明，本文提出的方法有望通过将肿瘤本身作为抗原来源，并引入R848@NPs/+NIR来产生长期抗肿瘤免疫力，从而原位生成癌症疫苗，用于个性化免疫治疗。
