Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, a member of the imCORE network, Baltimore, Maryland, USA.
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Clin Invest. 2024 Aug 29;134(20):e176567. doi: 10.1172/JCI176567.
BACKGROUNDImmune-related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). Prospective evaluation of the drivers of irAEs in a diverse pan-tumor cohort is needed to identify patients at greatest risk and to develop rational treatment and interception strategies.METHODSIn an observational study, we prospectively collected blood samples and performed regular clinical evaluations for irAEs in patients receiving ICI therapy as standard of care for solid tumors. We performed in-parallel analysis of cytokines by Luminex immunoassay and circulating immune cells by cytometry by time-of-flight (CyTOF) at baseline and on treatment to investigate mechanisms of irAEs.RESULTSWe enrolled 111 patients, of whom 40.5% developed a symptomatic irAE (grade ≥ 2). Development of a grade ≥ 2 irAE was positively associated with the use of combination ICI and a history of an autoimmune disorder. Early changes in T helper 17 (Th17) (IL-6, IL-17f), type 2 (IL-5, IL-13, IL-25), and type 1 (TNF-α) cytokine signatures and congruent on-treatment expansions of Th17 and Th2 effector memory (Th2EM) T cell populations in peripheral blood were positively associated with the development of grade ≥2 irAEs. IL-6 levels were also associated with inferior cancer-specific survival and overall survival.CONCLUSIONSIn a diverse, prospective pan-tumor cohort, Th17 and Th2 skewing during early ICI treatment was associated with the development of clinically relevant irAEs but not antitumor responses, providing possible targets for monitoring and therapeutic interventions.FUNDINGJohns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the NCI SPORE in Gastrointestinal Cancers (P50 CA062924), NCI grant (R50CA243627 to LD), the NIH Center Core Grant (P30 CA006973), Swim Across America (to MY), NIAMS (K23AR075872 to LC), and imCORE-Genentech grant 137515 (to Johns Hopkins Medicine on behalf of MY).
背景
免疫相关不良事件（irAEs）及其相关发病率/死亡率是接受免疫检查点抑制剂（ICI）治疗的患者的主要关注点。需要对不同肿瘤患者队列中导致 irAE 的驱动因素进行前瞻性评估，以确定风险最大的患者，并制定合理的治疗和干预策略。
方法
在一项观察性研究中，我们前瞻性地收集了接受 ICI 治疗的实体瘤患者的血液样本，并定期进行 irAE 的临床评估。我们在基线和治疗时通过 Luminex 免疫分析平行分析细胞因子，并通过时间飞行（CyTOF）流式细胞术分析循环免疫细胞，以研究 irAE 的机制。
结果
我们共纳入 111 例患者，其中 40.5%发生了有症状的 irAE（≥2 级）。≥2 级 irAE 的发生与联合使用 ICI 和自身免疫性疾病史有关。早期 T 辅助 17（Th17）（IL-6、IL-17f）、2 型（IL-5、IL-13、IL-25）和 1 型（TNF-α）细胞因子特征的变化以及外周血中 Th17 和 Th2 效应记忆（Th2EM）T 细胞群体的治疗相关扩增与≥2 级 irAE 的发生呈正相关。IL-6 水平也与癌症特异性生存率和总生存率降低有关。
结论
在一个多样化的、前瞻性的泛肿瘤队列中，ICI 治疗早期 Th17 和 Th2 偏倚与临床相关 irAE 的发生有关，但与抗肿瘤反应无关，这为监测和治疗干预提供了可能的靶点。
资助
约翰霍普金斯布隆伯格-金梅尔癌症免疫治疗研究所，NCI 胃肠道癌症 SPRORE（P50 CA062924），NCI 资助（R50CA243627 给 LD），NIH 中心核心资助（P30 CA006973），游泳穿越美国（给 MY），NIAMS（K23AR075872 给 LC），和 imCORE-Genentech 资助 137515（代表 MY 给约翰霍普金斯医学）。
