放疗调控吲哚胺-2,3-双加氧酶影响非小细胞肺癌患者免疫功能作用及机制研究

The clinical outcome of patients with lung cancer after radiation based therapy remained unsatisfactory. Radiation therapy can activate anti-tumor immunity by changing the immune and tumor microenvironment. The level of radiation immune activation may be closely related to the treatment outcome, but the basis and clinical evidence need to be confirmed. IDO (indoleamine-2,3-dioxygenase) is a well-known immunosuppressive factor. We demonstrated in 166 patients with non-small cell lung cancer that moderate and low-dose radiotherapy can significantly reduce IDO activity, higher dose radiation increased IDO activity in some patients, and post-treatment IDO levels were significantly correlated with overall survival and distant metastasis. In order to reveal the clinical value and significance of IDO in treatment outcome of patients after radiation based treatment, this project will address following questions: 1) to validate IDO levels of blood samples as a marker for radiation immune modulation in prospective patients and use mouse model to study the IDO and radiation dose effect, determine the best dose of maximal stimulation to confirm the clinical value of IDO as a potential molecular marker for diagnosis; 2) to study the interaction of IDO with other immunosuppressive pathways and explore the molecular mechanism of radiation-induced immune activation; 3) to explore the significance of IDO biomarkers in guiding combined radiotherapy and immunotherapy. This study will provide candidate biomarkers for clinical treatment of non-small cell lung cancer, and guide the clinical individualized guided radiotherapy or immunotherapy combined with lung cancer survival rate is improved.

放疗后肺癌患者的存活率仍然不理想。放疗通过改变免疫和肿瘤微环境激活抗肿瘤免疫性，免疫激活水平可能与治疗结果密切相关，但基础及临床依据亟待确证。吲哚胺-2,3-双加氧酶（IDO）是熟知的免疫抑制因子，我们前期研究在166名非小细胞肺癌（NSCLC）中证实了低剂量放疗可以显着降低IDO活性，改善患者生存和降低转移。为了揭示IDO对患者放疗后生存率预测的临床价值和重要意义，本项目拟开展：1）进一步分析前瞻性患者的血液标本IDO水平，及使用小鼠模型研究宽剂量范围内IDO和放疗剂量的关系，找到激活免疫的最佳放疗剂量，明确IDO作为潜在诊疗分子标志物的临床价值；2）深入探索IDO与其他免疫抑制通路的相互作用，探索放疗诱导免疫激活的分子机制；3）探索IDO对指导优化放疗联合免疫治疗的意义。本研究将为临床治疗NSCLC提供候选生物标志物，并指导临床个体化放疗或联合免疫治疗，从而提高NSCLC的生存率。

放射治疗是肺癌临床治疗的重要手段，然而目前的肿瘤控制及生存仍不理想。吲哚胺-2,3-双加氧酶（IDO）有免疫抑制功能，在放疗过程中存在动态变化可能与肺癌的预后密切相关。在本课题中，我们利用动物及临床研究阐明了不同分割剂量放疗下IDO的水平变化趋势，并发现了IDO对肺癌放疗及联合免疫治疗肿瘤控制的作用及分子机制。IDO在放疗过程中呈低剂量降低，高剂量升高的趋势，其放疗后或免疫治疗后的低水平可以提示肺癌患者更好的肿瘤控制效果及长期的生存。本研究证实IDO可以作为有效的生物标记物预测患者的预后，针对个体化放射治疗及免疫治疗提高肺癌整体疗效具有重要的理论意义。