Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, China.
Front Immunol. 2023 Mar 27;14:1124152. doi: 10.3389/fimmu.2023.1124152. eCollection 2023.
Residual lesions and undetectable metastasis after insufficient radiofrequency ablation (iRFA) are associated with earlier new metastases and poor survival in cancer patients, for induced aggressive tumor phenotype and immunosuppression. Programmed cell death protein 1(PD-1) blockade has been reported to enhance the radiofrequency ablation-elicited antitumor immunity, but its ability to eliminate incompletely ablated residual lesions has been questioned. Here, we report a combined treatment modality post iRFA based on integrating an oxygen self-enriching nanodrug PFH-Ce6 liposome@O nanodroplets (PCL@O)-augmented noninvasive sonodynamic therapy (SDT) with PD-1 blockade. PCL@O containing Ce6 as the sonosensitizer and PFH as O reservoir, was synthesized as an augmented SDT nanoplatform and showed increased ROS generation to raise effective apoptosis of tumor cells, which also exposed more calreticulin to induce stronger immunogenic cell death (ICD). Combining with PD-1 blockade post iRFA, this optimized SDT induced a better anti-tumor response in MC38 tumor bearing mouse model, which not only arrested residual primary tumor progression, but also inhibited the growth of distant tumor, therefore prolonging the survival. Profiling of immune populations within the tumor draining lymph nodes and tumors further revealed that combination therapy effectively induced ICD, and promoted the maturation of dendritic cells, tumor infiltration of T cells, as well as activation of cytotoxic T lymphocytes. While iRFA alone could result in an increase of regulatory T cells (Tregs) in the residual tumors, SDT plus PD-1 blockade post iRFA reduced the number of Tregs in both primary and distant tumors. Moreover, the combined treatment could significantly initiate long-term immune memory, manifesting as elevated levels of CD8 and CD4 central memory cells. Therefore, this study establishes the preclinical proof of concept to apply oxygen self-enriching SDT to augment cancer immunotherapy after iRFA.
射频消融不完全(iRFA)后的残留病灶和无法检测到的转移与癌症患者更早出现新转移和较差的生存相关,这与诱导侵袭性肿瘤表型和免疫抑制有关。程序性细胞死亡蛋白 1(PD-1)阻断已被报道可增强射频消融引发的抗肿瘤免疫,但它消除不完全消融的残留病灶的能力受到质疑。在这里,我们报告了一种基于整合富含氧纳米药物 PFH-Ce6 脂质体@O 纳米液滴(PCL@O)增强的非侵入性声动力学疗法(SDT)与 PD-1 阻断的 iRFA 后联合治疗模式。PCL@O 含有作为声敏剂的 Ce6 和作为 O 储库的 PFH,被合成作为增强的 SDT 纳米平台,显示出增加的 ROS 生成以提高肿瘤细胞的有效凋亡,这也暴露了更多的钙网蛋白以诱导更强的免疫原性细胞死亡(ICD)。与 iRFA 后 PD-1 阻断相结合,这种优化的 SDT 在 MC38 荷瘤小鼠模型中引起了更好的抗肿瘤反应,不仅阻止了残留原发性肿瘤的进展,而且抑制了远处肿瘤的生长,从而延长了生存期。对肿瘤引流淋巴结和肿瘤内免疫群体的分析进一步表明,联合治疗有效地诱导了 ICD,并促进了树突状细胞的成熟、肿瘤浸润 T 细胞以及细胞毒性 T 淋巴细胞的激活。虽然 iRFA 本身可导致残留肿瘤中调节性 T 细胞(Tregs)的增加,但 SDT 加 iRFA 后 PD-1 阻断减少了原发性和远处肿瘤中 Tregs 的数量。此外,联合治疗可显著引发长期免疫记忆,表现为 CD8 和 CD4 中央记忆细胞水平升高。因此,本研究为应用富含氧的 SDT 增强 iRFA 后癌症免疫治疗提供了临床前概念验证。