Department of Intensive Care and Thoracic Oncology, Jules Bordet Institute, Centre des Tumeurs de l'Université Libre de Bruxelles (ULB), ULB, Brussels, Belgium.
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Nature. 2019 Jul;571(7766):570-575. doi: 10.1038/s41586-019-1330-0. Epub 2019 Jun 26.
Early detection and treatment are critical for improving the outcome of patients with cancer. Understanding the largely uncharted biology of carcinogenesis requires deciphering molecular processes in premalignant lesions, and revealing the determinants of the intralesional immune reaction during cancer development. The adaptive immune response within tumours has previously been shown to be strongest at the earliest stage of carcinoma. Here we show that immune activation and immune escape occur before tumour invasion, and reveal the relevant immune biomarkers of the pre-invasive stages of carcinogenesis in the lung. We used gene-expression profiling and multispectral imaging to analyse a dataset of 9 morphological stages of the development of lung squamous cell carcinoma, which includes 122 well-annotated biopsies from 77 patients. We identified evolutionary trajectories of cancer and immune pathways that comprise (1) a linear increase in proliferation and DNA repair from normal to cancerous tissue; (2) a transitory increase of metabolism and early immune sensing, through the activation of resident immune cells, in low-grade pre-invasive lesions; (3) the activation of immune responses and immune escape through immune checkpoints and suppressive interleukins from high-grade pre-invasive lesions; and, ultimately, (4) the activation of the epithelial-mesenchymal transition in the invasive stage of cancer. We propose that carcinogenesis in the lung involves a dynamic co-evolution of pre-invasive bronchial cells and the immune response. These findings highlight the need to develop immune biomarkers for early detection as well as immunotherapy-based chemopreventive approaches for individuals who are at high risk of developing lung cancer.
早期发现和治疗对于改善癌症患者的预后至关重要。要了解致癌作用的大部分未知生物学特性，就需要解析癌前病变中的分子过程，并揭示癌症发展过程中肿瘤内免疫反应的决定因素。肿瘤内适应性免疫反应以前被认为在癌的最早阶段最强。在这里，我们表明免疫激活和免疫逃逸发生在肿瘤侵袭之前，并揭示了肺癌癌前阶段的相关免疫生物标志物。我们使用基因表达谱和多光谱成像分析了一个肺鳞状细胞癌发展的 9 个形态学阶段的数据集，该数据集包括 77 名患者的 122 个有明确注释的活检样本。我们确定了癌症和免疫途径的进化轨迹，包括：（1）从正常组织到癌变组织，增殖和 DNA 修复呈线性增加；（2）在低级别癌前病变中，通过激活常驻免疫细胞，代谢和早期免疫感应短暂增加；（3）在高级别癌前病变中，通过免疫检查点和抑制性白细胞介素激活免疫反应和免疫逃逸；最终，（4）在癌症侵袭阶段激活上皮-间充质转化。我们提出，肺部的癌变涉及到癌前支气管细胞和免疫反应的动态共同进化。这些发现强调了需要开发用于早期检测的免疫生物标志物，以及针对有发展为肺癌高风险的个体的基于免疫疗法的化学预防方法。
