Bardoscia Lilia, Pasinetti Nadia, Triggiani Luca, Cozzi Salvatore, Sardaro Angela
Radiation Oncology Unit, S. Luca Hospital, Healthcare Company Tuscany Nord Ovest, Lucca, Italy.
Radiation Oncology Department, ASST Valcamonica Esine and University of Brescia, Brescia, Italy.
Front Pharmacol. 2021 Nov 1;12:746853. doi: 10.3389/fphar.2021.746853. eCollection 2021.
Immune checkpoint inhibitors have gained an established role in the treatment of different tumors. Indeed, their use has dramatically changed the landscape of cancer care, especially for tumor types traditionally known to have poor outcomes. However, stimulating anticancer immune responses may also elicit an unusual pattern of immune-related adverse events (irAEs), different from those of conventional chemotherapy, likely due to a self-tolerance impairment featuring the production of autoreactive lymphocytes and autoantibodies, or a non-specific autoinflammatory reaction. Ionizing radiation has proven to promote both positive pro-inflammatory and immunostimolatory activities, and negative anti-inflammatory and immunosuppressive mechanisms, as a result of cross-linked interactions among radiation dose, the tumor microenvironment and the host genetic predisposition. Several publications argue in favor of combining immunotherapy and a broad range of radiation schedules, based on the recent evidence of superior treatment responses and patient survival. The synergistic modulation of the immune response by radiation therapy and immunotherapeutics, particularly those manipulating T-cell activation, may also affect the type and severity of irAEs, suggesting a relationship between the positive antitumor and adverse autoimmune effects of these agents. As yet, information on factors that may help to predict immune toxicity is still lacking. The aim of our work is to provide an overview of the biological mechanisms underlying irAEs and possible crosslinks with radiation-induced anticancer immune responses. We believe such an overview may support the optimization of immunotherapy and radiotherapy as essential components of multimodal anticancer therapeutic approaches. Challenges in translating these to clinical practice are discussed.
免疫检查点抑制剂在不同肿瘤的治疗中已确立了其作用。事实上，它们的使用极大地改变了癌症治疗的格局，尤其是对于传统上预后较差的肿瘤类型。然而，刺激抗癌免疫反应也可能引发一种不同于传统化疗的特殊免疫相关不良事件（irAE）模式，这可能是由于自身耐受性受损，其特征是产生自身反应性淋巴细胞和自身抗体，或者是一种非特异性的自身炎症反应。由于辐射剂量、肿瘤微环境和宿主遗传易感性之间的交联相互作用，电离辐射已被证明既能促进积极的促炎和免疫刺激活性，也能促进消极的抗炎和免疫抑制机制。基于近期有关治疗反应更佳和患者生存率提高的证据，一些出版物主张将免疫疗法与多种放疗方案相结合。放疗和免疫疗法，尤其是那些操纵T细胞活化的疗法，对免疫反应的协同调节也可能影响irAE的类型和严重程度，这表明这些药物的积极抗肿瘤作用和不良自身免疫作用之间存在关联。然而，目前仍缺乏有助于预测免疫毒性的因素的相关信息。我们这项工作的目的是概述irAE背后的生物学机制以及与辐射诱导的抗癌免疫反应可能存在的交叉联系。我们相信这样的概述可能有助于优化免疫疗法和放射疗法，使其成为多模式抗癌治疗方法的重要组成部分。本文还讨论了将这些研究成果转化为临床实践所面临的挑战。
