Enhanced Anti-Tumor Efficacy through a Combination of Integrin αvβ6-Targeted Photodynamic Therapy and Immune Checkpoint Inhibition.
Enhanced Anti-Tumor Efficacy through a Combination of Integrin αvβ6-Targeted Photodynamic Therapy and Immune Checkpoint Inhibition.
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作者：
Gao L;Zhang C;Gao D;Liu H;Yu X;Lai J;Wang F;Lin J;Liu Z
“训练”宿主免疫系统以识别和系统地消除残留的肿瘤病变和微转移是癌症治疗的一种有前途的策略。在本研究中，我们探讨了整合素αvβ6靶向光动力疗法能否触发宿主免疫应答，以及光动力疗法联合抗PD-1免疫检查点抑制能否有效治疗原发肿瘤和转移瘤。通过近红外荧光成像，DSAB-HK被证明能够特异性地靶向4T1小鼠乳腺癌模型中的皮下肿瘤或稳定转染4T1(4T1-flc)肺转移瘤的萤火虫荧光素酶。在光照条件下，DSAB-HK的PDT能显著抑制皮下4T1肿瘤的生长，促进树突状细胞的成熟和细胞因子的产生，从而刺激CD8+细胞毒性T细胞的募集。此外，第一个肿瘤的DSAB-HK PDT和PD-1的阻断显著抑制了第二个皮下肿瘤的生长，并通过系列生物发光成像显示，也减缓了4T1-Fluc肺转移的生长。综上所述，我们的结果证实了肿瘤靶向PDT和免疫检查点抑制在提高抗肿瘤免疫和抑制肿瘤生长/转移方面的协同效应。
“Training” the host immune system to recognize and systemically eliminate residual tumor lesions and micrometastases is a promising strategy for cancer therapy. In this study, we investigated whether integrin αvβ6-targeted photodynamic therapy (PDT) of tumors using a phthalocyanine dye-labeled probe (termed DSAB-HK) could trigger the host immune response, and whether PDT in combination with anti-PD-1 immune checkpoint inhibition could be used for the effective therapy of primary tumors and metastases. By near-infrared fluorescence imaging, DSAB-HK was demonstrated to specifically target either subcutaneous tumors in a 4T1 mouse breast cancer model or firefly luciferase stably transfected 4T1 (4T1-fLuc) lung metastatic tumors. Upon light irradiation, PDT by DSAB-HK significantly inhibited the growth of subcutaneous 4T1 tumors, and in addition promoted the maturation of dendritic cells and their production of cytokines, which subsequently stimulated the tumor recruitment of CD8+ cytotoxic T lymphocytes. Furthermore, DSAB-HK PDT of the first tumor followed by PD-1 blockade markedly suppressed the growth of a second subcutaneous tumor, and also slowed the growth of 4T1-fLuc lung metastasis as demonstrated by serial bioluminescence imaging. Together, our results demonstrated the synergistic effect of tumor-targeted PDT and immune checkpoint inhibition for improving anti-tumor immunity and suppressing tumor growth/metastasis.