Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
Curr Cancer Drug Targets. 2024;24(6):642-653. doi: 10.2174/0115680096261142231018104854.
BACKGROUND: Immune-checkpoint inhibitors (ICIs) against programmed death (PD)-1/PD-L1 pathway immunotherapy have been demonstrated to be effective in only a subset of patients with cancer, while the rest may exhibit low response or may develop drug resistance after initially responding. Previous studies have indicated that extensive collagen-rich stroma secreted by cancer-associated fibroblasts (CAFs) within the tumor microenvironment is one of the key obstructions of the immunotherapy for some tumors by decreasing the infiltrating cytotoxic T cells. However, there is still a lack of effective therapeutic strategies to control the extracellular matrix by targeting CAFs. METHODS: The enhanced uptake of IR-780 by CAFs was assessed by using in vivo or ex vivo nearinfrared fluorescence imaging, confocal NIR fluorescent imaging, and CAFs isolation testing. The fibrotic phenotype down-regulation effects and CAFs killing effect of IR-780 were tested by qPCR, western blot, and flow cytometry. The therapeutic enhancement of anti-PD-L1 by IR-780 was evaluated on EMT6 and MC38 subcutaneous xenograft mice models. RESULTS: IR-780 has been demonstrated to be preferentially taken up by CAFs and accumulate in the mitochondria. Further results identified low-dose IR-780 to downregulate the fibrotic phenotype, while high-dose IR-780 could directly kill both CAFs and EMT6 cells in vitro. Moreover, IR-780 significantly inhibited extracellular matrix (ECM) protein deposition in the peri-tumoral stroma on subcutaneous EMT6 and MC38 xenografts, which increased the proportion of tumor-infiltrating lymphocytes (TILs) in the deep tumor and further promoted anti-PD-L1 therapeutic efficacy. CONCLUSION: This work provides a unique strategy for the inhibition of ECM protein deposition in the tumor microenvironment by targeted regulating of CAFs, which destroys the T cell barrier and further promotes tumor response to PD-L1 monoclonal antibody. IR-780 has been proposed as a potential therapeutic small-molecule adjuvant to promote the effect of immunotherapy.
背景：针对程序性死亡（PD）-1/PD-L1 通路免疫疗法的免疫检查点抑制剂（ICIs）已被证明仅对部分癌症患者有效，而其余患者可能反应不佳或在最初反应后产生耐药性。先前的研究表明，肿瘤微环境中癌症相关成纤维细胞（CAFs）分泌的广泛富含胶原的基质是某些肿瘤免疫治疗的主要障碍之一，因为它会减少浸润性细胞毒性 T 细胞。然而，目前仍然缺乏有效的治疗策略来通过靶向 CAFs 来控制细胞外基质。
方法：通过体内或离体近红外荧光成像、共聚焦 NIR 荧光成像和 CAFs 分离测试评估 CAFs 对 IR-780 的摄取增强情况。通过 qPCR、western blot 和流式细胞术测试 IR-780 对纤维化表型的下调作用和 CAFs 的杀伤作用。在 EMT6 和 MC38 皮下异种移植小鼠模型上评估了 IR-780 对抗 PD-L1 的治疗增强作用。
结果：IR-780 已被证明优先被 CAFs 摄取并在其线粒体中积累。进一步的结果表明，低剂量的 IR-780 可下调纤维化表型，而高剂量的 IR-780 可直接杀伤 CAFs 和 EMT6 细胞。此外，IR-780 可显著抑制皮下 EMT6 和 MC38 异种移植瘤周围基质中细胞外基质（ECM）蛋白的沉积，增加肿瘤深部浸润的淋巴细胞（TILs）比例，并进一步促进抗 PD-L1 的治疗效果。
结论：这项工作提供了一种通过靶向调节 CAFs 抑制肿瘤微环境中细胞外基质沉积的独特策略，破坏了 T 细胞屏障，进一步促进了肿瘤对 PD-L1 单克隆抗体的反应。IR-780 已被提议作为一种潜在的治疗性小分子佐剂，以增强免疫治疗的效果。
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