Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Front Immunol. 2020 Jun 10;11:999. doi: 10.3389/fimmu.2020.00999. eCollection 2020.
Cancer-associated fibroblasts (CAFs) were associated with tumor progression in the tumor microenvironment (TME). However, their immunosuppressive roles in protecting cancer cells from the attack by cytotoxic T lymphocytes (CTLs) are not fully clear. In this study, we investigated whether and how CAFs regulate tumor-infiltrating lymphocytes as well as their role in tumor immunosuppression. Eighty-three cases of ovarian cancer and 10 controls were analyzed for CAFs and CD8+ tumor-infiltrating lymphocytes by gene array and immunohistochemistry. We evaluated presenilin 1 (PS1) expression in CAFs, CTL penetration, tumor burden, dendritic cell function, and migration of tumor-infiltrating lymphocytes and their function and after silencing PS1. In addition, the pathway via which PS1 affects the TME was also evaluated. PS1 was highly expressed in CAFs, and its silencing significantly promoted CD8+ CTL proliferation and penetration in multiple ovarian models ( < 0.05), resulting in tumor regression and growth inhibition. Interleukin (IL)-1β was identified as a major immune inhibitor in the TME, and it was significantly decreased after PS1 silencing ( < 0.05), which was regulated by the WNT/β-catenin pathway. It was also showed that high expression of IL-1β in CAFs inhibits CTL penetration significantly ( < 0.05). Highly expressed PS1 in CAFs plays a crucial role in regulating tumor-infiltrating lymphocyte populations in the TME via the WNT/β-catenin pathway. Targeting PS1 may retrieve functional CTLs in the TME and improve the efficacy of current immunotherapies.
癌相关成纤维细胞（CAFs）与肿瘤微环境（TME）中的肿瘤进展有关。然而，它们在保护癌细胞免受细胞毒性 T 淋巴细胞（CTL）攻击方面的免疫抑制作用尚不完全清楚。在这项研究中，我们研究了 CAFs 是否以及如何调节肿瘤浸润淋巴细胞及其在肿瘤免疫抑制中的作用。通过基因阵列和免疫组织化学分析了 83 例卵巢癌病例和 10 例对照的 CAFs 和 CD8+肿瘤浸润淋巴细胞。我们评估了 CAFs 中早老素 1（PS1）的表达、CTL 穿透、肿瘤负担、树突状细胞功能以及肿瘤浸润淋巴细胞的迁移及其功能，以及沉默 PS1 后的情况。此外，还评估了 PS1 影响 TME 的途径。PS1 在 CAFs 中高表达，其沉默显著促进了多种卵巢模型中 CD8+CTL 的增殖和穿透（<0.05），导致肿瘤消退和生长抑制。白细胞介素（IL）-1β被鉴定为 TME 中的主要免疫抑制剂，沉默 PS1 后其表达显著降低（<0.05），这受 WNT/β-catenin 通路调节。还表明，CAFs 中高表达的 IL-1β显著抑制 CTL 穿透（<0.05）。CAFs 中高表达的 PS1 通过 WNT/β-catenin 通路在调节 TME 中的肿瘤浸润淋巴细胞群方面发挥关键作用。靶向 PS1 可能会在 TME 中恢复功能性 CTL，并提高当前免疫疗法的疗效。
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