Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, China; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Pharmacol Res. 2021 Oct;172:105811. doi: 10.1016/j.phrs.2021.105811. Epub 2021 Aug 12.
BACKGROUND/AIMS: IR700DX-6T and IR700DX-mbc94 are two chemically synthesized photosensitizers (PSs) that target the translocator protein (TSPO) and type 2 cannabinoid receptor (CBR), respectively, for photodynamic therapy (PDT) of cancer. Recently, we found that IR700DX-6T and IR700DX-mbc94 exhibited high selectivity and efficiency in PDT for breast cancer and malignant astrocytoma. Yet, the phototherapeutic effects of the PSs on pancreatic cancer and underlying mechanisms remain unknown. This study investigated the effect of IR700DX-6T- or IR700DX-mbc94-PDT on pancreatic cancer and whether the treatment involves eliciting anticancer immune responses in support of superior therapeutic efficacy.
Four pancreatic cancer cell lines were used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies regarding the therapeutic effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT on pancreatic cancer. The immunostimulatory or immunosuppressive effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT were examined by detecting CD8 T cells, regulatory T cells (T), and dendritic cells (DCs) using flow cytometry and immunohistochemistry (IHC).
TSPO and CBR were markedly upregulated in pancreatic cancer cells and tissues. Both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. Notably, assessment of anticancer immune responses revealed that both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly induced CD8 T cells, promoted maturation of DCs, and suppressed T, with stronger effects exerted by IR700DX-6T-PDT compared to IR700DX-mbc94-PDT.
IR700DX-6T-PDT and IR700DX-mbc94-PDT involves eliciting anticancer immune responses. Our study has also implicated that PDT in combination with immunotherapy holds promise to improve therapeutic efficacy for patients with pancreatic cancer.
背景/目的：IR700DX-6T 和 IR700DX-mbc94 是两种分别针对转位蛋白（TSPO）和 2 型大麻素受体（CBR）的化学合成光敏剂（PS），用于癌症的光动力疗法（PDT）。最近，我们发现 IR700DX-6T 和 IR700DX-mbc94 在乳腺癌和恶性星形细胞瘤的 PDT 中具有高选择性和高效率。然而，PS 对胰腺癌的光疗效果及其潜在机制尚不清楚。本研究探讨了 IR700DX-6T 或 IR700DX-mbc94-PDT 对胰腺癌的治疗作用，以及治疗是否涉及引发抗癌免疫反应以支持更好的治疗效果。
使用四种胰腺癌细胞系进行体外研究。使用 C57BL/6 小鼠生成胰腺癌细胞衍生的异种移植物，用于研究 IR700DX-6T-PDT 和 IR700DX-mbc94-PDT 对胰腺癌的治疗效果。通过流式细胞术和免疫组织化学（IHC）检测 CD8 T 细胞、调节性 T 细胞（T）和树突状细胞（DC）来检测 IR700DX-6T-PDT 和 IR700DX-mbc94-PDT 的免疫刺激或免疫抑制作用。
TSPO 和 CBR 在胰腺癌细胞和组织中明显上调。IR700DX-6T-PDT 和 IR700DX-mbc94-PDT 均以剂量和时间依赖性方式显著抑制胰腺癌细胞生长。值得注意的是，对抗癌免疫反应的评估表明，IR700DX-6T-PDT 和 IR700DX-mbc94-PDT 均显著诱导 CD8 T 细胞，促进 DC 成熟，并抑制 T，IR700DX-6T-PDT 的作用强于 IR700DX-mbc94-PDT。
IR700DX-6T-PDT 和 IR700DX-mbc94-PDT 涉及引发抗癌免疫反应。我们的研究还表明，PDT 联合免疫疗法有望提高胰腺癌患者的治疗效果。
