Dual mitigation of immunosuppression combined with photothermal inhibition for highly effective primary tumor and metastases therapy
Dual mitigation of immunosuppression combined with photothermal inhibition for highly effective primary tumor and metastases therapy
复制标题
双重缓解免疫抑制与光热抑制相结合，实现高效原发肿瘤和转移瘤治疗
DOI：
10.1016/j.biomaterials.2021.120856
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发表时间：
2021-05-11
期刊：
影响因子：
14
通讯作者：
Li, Rui
中科院分区：
文献类型：
--
作者：
Huang, Ju;Zhang, Liang;Li, Rui
当某些免疫检查点（例如，PD-1/PD-L1）被阻断。不幸的是，PD-1/PD-L1阻断仅引起有限的免疫应答，因为肿瘤反应性T淋巴细胞的分化通常被TGF-β途径抑制。也就是说，对抗癌症的武器被削弱了。在本研究中，除了采用光热疗法（PTT）消除原发肿瘤外，我们还旨在原位暴露肿瘤相关抗原并发挥免疫反应以抑制转移。这种增强的免疫策略通过基于IR 780/SB-505124的纳米脂质体（Nano-IR-SB@Lip）实现。在施用后，TGF-β途径被SB抑制以驱动效应T细胞进入应答状态并减少Treg细胞的浸润，最终大大增强抗癌武器。同时，肿瘤细胞的免疫抑制“保护”也通过阻断PD 1/PD-L1免疫检查点而被中和。凭借IR 780的固有特性，Nano-IR-SB@Lip可选择性蓄积，深入肿瘤组织，并优先保留在线粒体中。上述特征对肿瘤治疗至关重要。因此，通过Nano-IR-SB@Lip在肿瘤中的选择性积累/深度渗透，实现PTT诱导的免疫原性细胞死亡和免疫抑制策略的双重缓解（TGF-β抑制/PD-1/PD-L1阻断），实现了高效的癌症免疫治疗，这是一种有前景的癌症治疗方式。
T-cell based immune response can attack cancer cells formidably when certain immune checkpoint (e.g., PD-1/PD-L1) is blocked. Unfortunately, PD-1/PD-L1 blockade only provoke limited immune response because the differentiation of tumor-reactive T lymphocytes is often suppressed by TGF-beta pathway. Namely, the combating cancer weapon is weakened. In this study, other than employing photothermal therapy (PTT) to eliminate the primary tumor, we also aimed to expose in situ tumor-associated antigens and exert immune response for metastases inhibition. This enhanced immunotherapeutic strategy is achieved by IR780/SB-505124 based nanoliposomes (Nano-IR-SB@Lip). Upon administration, TGF-beta pathway is inhibited by SB to drive effector T cells into a responsive state and reduce the infiltration of Treg cells, eventually greatly enhancing the weapon against cancer. In the meantime, the immunosuppressive "protection" of tumor cells is also neutralized by blocking PD1/PD-L1 immune checkpoint. By virtue of inherent characteristics of IR780, Nano-IR-SB@Lip can selectively accumulate, penetrate deeply in tumor tissues, and preferentially retain in mitochondria. The above features are of critical importance to tumor therapy. Thus, highly effective cancer immunotherapy is implemented via selective accumulation/deep penetration of Nano-IR-SB@Lip in tumor, achieving PTT induced immunogenic cell death and dual mitigation of immunosuppression strategy (TGF-beta inhibition/PD-1/PD-L1 blockade), which is a promising therapeutic modality for cancer.