Immunodeficiency Unit and Immunological Diagnostics Laboratory, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
Research Unit Pediatric Hematology and Immunology, Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria.
J Allergy Clin Immunol. 2018 Jan;141(1):59-68.e4. doi: 10.1016/j.jaci.2017.06.009. Epub 2017 Jun 29.
Malignancies occur with a higher incidence rate and manifest earlier in life in patients with primary immunodeficiency disorders (PIDs) than in the general population. However, no universal mechanism of malignancy predisposition in patients with PIDs has been determined. Despite strong support for the physiologic role of tumor immunosurveillance and the increasing success of strategies in immunologic tumor therapy, which include checkpoint inhibition, mAbs, and engineered T-cell antigen receptors, the incidence and pattern of malignancies in patients with PIDs do not reflect an increased tumor immune escape per se. In contrast, malignancies appear to be restricted to either (1) tissue types bearing the same molecular defect that underlies the PID, such as syndromes of DNA repair deficiency or immune cell-specific maturation or functional defects that suggest a cell-intrinsic oncogenic basis, or (2) other tissues when they are infected by transforming viruses or chronically inflamed, pointing toward extrinsic causes for transformation that are potentially facilitated by but not predominantly caused by a lack of immunosurveillance. Based on recent studies of pre-existing conditions in patients with malignancies and on malignancies in large PID cohorts, we conclude that a large part of tumor predisposition in patients with PIDs is derived from the same molecular defect as the immunodeficiency itself. The presented concept elucidates diverse pathomechanisms and risks of malignancies in patients with PIDs in light of current tumor immune therapies.
原发性免疫缺陷病（PID）患者的恶性肿瘤发病率更高，且发病年龄更早。然而，目前尚未确定 PID 患者恶性肿瘤易感性的普遍机制。尽管肿瘤免疫监视的生理作用得到了强有力的支持，免疫肿瘤治疗策略（包括检查点抑制、单抗和工程化 T 细胞抗原受体）也越来越成功，但 PID 患者的恶性肿瘤发病率和模式并不反映肿瘤免疫逃逸的增加。相反，恶性肿瘤似乎仅限于（1）存在导致 PID 的相同分子缺陷的组织类型，例如 DNA 修复缺陷综合征或免疫细胞特异性成熟或功能缺陷，提示存在细胞内在致癌基础，或（2）当它们被转化病毒感染或慢性炎症时，指向转化的外在原因，这些原因可能是由免疫监视缺失促进的，但不是主要由其引起的。基于对恶性肿瘤患者和大型 PID 队列中恶性肿瘤的现有情况的研究，我们得出结论，PID 患者的肿瘤易感性很大一部分源自与免疫缺陷本身相同的分子缺陷。鉴于当前的肿瘤免疫治疗，本研究提出的概念阐明了 PID 患者恶性肿瘤的多种发病机制和风险。
