Gockeln Lena, Wirsdörfer Florian, Jendrossek Verena
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
Front Cell Dev Biol. 2025 Jan 13;12:1471072. doi: 10.3389/fcell.2024.1471072. eCollection 2024.
Consolidation with PD-1/PD-L1-based immune checkpoint blockade after concurrent platinum-based chemo-radiotherapy has become the new standard of care for advanced stage III unresectable non-small cell lung cancer (NSCLC) patients. In order to further improve therapy outcomes, innovative combinatorial treatment strategies aim to target additional immunosuppressive barriers in the tumor microenvironment such as the CD73/adenosine pathway. CD73 and adenosine are known as crucial endogenous regulators of lung homeostasis and inflammation, but also contribute to an immunosuppressive tumor microenvironment. Furthermore, the CD73/adenosine pathway can also limit the immune-activating effects of cytotoxic therapies by degrading the pro-inflammatory danger molecule ATP, which is released into the tumor microenvironment and normal lung tissue upon therapy-induced cell damage. Thus, while targeting CD73 may enhance the efficacy of radio-immunotherapies in cancer treatment by mitigating tumor immune escape and improving immune-mediated tumor killing, it also raises concerns about increased immune-related adverse events (irAEs) in the normal tissue. In fact, combined radio-immunotherapies bear an increased risk of irAEs in the lungs, and additional pharmacologic inhibition of CD73 may further enhance the risk of overwhelming or overlapping pulmonary toxicity and thereby limit therapy outcome. This review explores how therapeutic interventions targeting CD73/adenosine dynamics could enhance radiation-induced immune activation in combined radio-immunotherapies, whilst potentially driving irAEs in the lung. We specifically investigate the interactions between radiotherapy and the CD73/adenosine pathway in radiation pneumonitis. Additionally, we compare the incidence of (radiation) pneumonitis reported in relevant trials to determine if there is an increased risk of irAEs in the clinical setting. By understanding these dynamics, we aim to inform future strategies for optimizing radio-immunotherapy regimens, ensuring effective cancer control while preserving pulmonary integrity and patient quality of life.
对于晚期不可切除的 III 期非小细胞肺癌（NSCLC）患者，在基于铂类的同步放化疗后联合使用基于 PD-1/PD-L1 的免疫检查点阻断疗法已成为新的标准治疗方案。为了进一步提高治疗效果，创新的联合治疗策略旨在针对肿瘤微环境中其他免疫抑制屏障，如 CD73/腺苷途径。CD73 和腺苷是肺内稳态和炎症的关键内源性调节因子，但也有助于形成免疫抑制性肿瘤微环境。此外，CD73/腺苷途径还可通过降解促炎危险分子 ATP 来限制细胞毒性疗法的免疫激活作用，ATP 在治疗诱导的细胞损伤后释放到肿瘤微环境和正常肺组织中。因此，虽然靶向 CD73 可能通过减轻肿瘤免疫逃逸和改善免疫介导的肿瘤杀伤来提高癌症治疗中放射免疫疗法的疗效，但也引发了对正常组织中免疫相关不良事件（irAEs）增加的担忧。事实上，联合放射免疫疗法会增加肺部发生 irAEs 的风险，对 CD73 的额外药物抑制可能会进一步增加严重或重叠性肺毒性的风险，从而限制治疗效果。本综述探讨了针对 CD73/腺苷动态变化的治疗干预如何在联合放射免疫疗法中增强辐射诱导的免疫激活，同时可能引发肺部的 irAEs。我们特别研究了放疗与放射性肺炎中 CD73/腺苷途径之间的相互作用。此外，我们比较了相关试验中报告的（放射性）肺炎发生率，以确定在临床环境中 irAEs 的风险是否增加。通过了解这些动态变化，我们旨在为优化放射免疫治疗方案的未来策略提供信息，确保在保持肺完整性和患者生活质量的同时有效控制癌症。
