Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Québec, Canada.
PLoS One. 2021 Nov 30;16(11):e0260636. doi: 10.1371/journal.pone.0260636. eCollection 2021.
Lung cancer is the leading cause of cancer-related deaths. While the recent use of immune checkpoint inhibitors significantly improves patient outcomes, responsiveness remains restricted to a small proportion of patients. Conventional dendritic cells (DCs) play a major role in anticancer immunity. In mice, two subpopulations of DCs are found in the lung: DC2s (CD11b+Sirpα+) and DC1s (CD103+XCR1+), the latest specializing in the promotion of anticancer immune responses. However, the impact of lung cancer on DC populations and the consequent influence on the anticancer immune response remain poorly understood. To address this, DC populations were studied in murine models of Lewis Lung Carcinoma (LLC) and melanoma-induced lung metastasis (B16F10). We report that direct exposure to live or dead cancer cells impacts the capacity of DCs to differentiate into CD103+ DC1s, leading to profound alterations in CD103+ DC1 proportions in the lung. In addition, we observed the accumulation of CD103loCD11b+ DCs, which express DC2 markers IRF4 and Sirpα, high levels of T-cell inhibitory molecules PD-L1/2 and the regulatory molecule CD200. Finally, DC1s were injected in combination with an immune checkpoint inhibitor (anti-PD-1) in the B16F10 model of resistance to the anti-PD-1 immune checkpoint therapy; the co-injection restored sensitivity to immunotherapy. Thus, we demonstrate that lung tumor development leads to the accumulation of CD103loCD11b+ DCs with a regulatory potential combined with a reduced proportion of highly-specialized antitumor CD103+ DC1s, which could promote cancer growth. Additionally, promoting an anticancer DC signature could be an interesting therapeutic avenue to increase the efficacy of existing immune checkpoint inhibitors.
肺癌是癌症相关死亡的主要原因。虽然最近使用免疫检查点抑制剂显著改善了患者的预后，但反应性仍然局限于一小部分患者。传统树突状细胞（DC）在抗癌免疫中发挥主要作用。在小鼠中，肺部存在两种亚群的 DC：DC2（CD11b+Sirpα+）和 DC1（CD103+XCR1+），后者专门促进抗癌免疫反应。然而，肺癌对 DC 群体的影响以及对抗癌免疫反应的后续影响仍知之甚少。为了解决这个问题，研究了 Lewis 肺癌（LLC）和黑色素瘤诱导的肺转移（B16F10）小鼠模型中的 DC 群体。我们报告说，直接暴露于活或死癌细胞会影响 DC 分化为 CD103+DC1 的能力，导致肺部 CD103+DC1 比例发生深刻变化。此外，我们观察到 CD103loCD11b+DC 的积累，其表达 DC2 标志物 IRF4 和 Sirpα，高水平的 T 细胞抑制分子 PD-L1/2 和调节分子 CD200。最后，在 B16F10 抵抗抗 PD-1 免疫检查点治疗的模型中，将 DC1 与免疫检查点抑制剂（抗 PD-1）联合注射；共注射恢复了对免疫治疗的敏感性。因此，我们证明了肺部肿瘤的发展导致具有调节潜力的 CD103loCD11b+DC 的积累，同时具有高度专业化的抗肿瘤 CD103+DC1 比例降低，这可能促进癌症生长。此外，促进抗癌 DC 特征可能是增加现有免疫检查点抑制剂疗效的一个有趣的治疗途径。
