BCG 膀胱内灌注治疗非肌层浸润性膀胱癌可诱导获得性免疫，降低呼吸道感染风险。

Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections.

机构信息

Department of Internal Medicine, Radboudumc, Nijmegen, The Netherlands.

Department for Health Evidence, Radboudumc, Nijmegen, The Netherlands.

出版信息

J Immunother Cancer. 2023 Jan;11(1). doi: 10.1136/jitc-2022-005518.

DOI:10.1136/jitc-2022-005518

PMID:36693678

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9884868/

Abstract

BACKGROUND

BCG is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity.

METHODS

The aim of this research was to determine whether BCG immunotherapy induces trained immunity in NMIBC patients. We conducted a prospective observational cohort study in 17 NMIBC patients scheduled for BCG therapy and measured trained immunity parameters at 9 time points before and during a 1-year BCG maintenance regimen. Ex vivo cytokine production by peripheral blood mononuclear cells, epigenetic modifications, and changes in the monocyte transcriptome were measured. The frequency of respiratory infections was investigated in two larger cohorts of BCG-treated and non-BCG treated NMIBC patients as a surrogate measurement of trained immunity. Gene-based association analysis of genetic variants in candidate trained immunity genes and their association with recurrence-free survival and progression-free survival after BCG therapy was performed to investigate the hypothesized link between trained immunity and clinical response.

RESULTS

We found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1β after heterologous ex vivo stimulation of circulating monocytes 6-12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40 to 1.01)) for respiratory infections in BCG-treated versus non-BCG-treated NMIBC patients. An epigenomics approach combining chromatin immuno precipitation-sequencing and RNA-sequencing with in vitro trained immunity experiments identified enhanced inflammasome activity in BCG-treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC.

CONCLUSION

We conclude that BCG immunotherapy induces trained immunity in NMIBC patients and this may account for the protective effects against respiratory infections. The data of our gene-based association analysis suggest that a link between trained immunity and oncological outcome may exist. Future studies should further investigate how trained immunity affects the antitumor immune responses in BCG-treated NMIBC patients.

摘要

背景

卡介苗（BCG）被推荐作为膀胱内免疫疗法，以降低非肌肉浸润性膀胱癌（NMIBC）患者的肿瘤复发风险。目前尚不清楚膀胱内 BCG 应用是否会诱导训练免疫。

方法

本研究旨在确定 NMIBC 患者的 BCG 免疫疗法是否会诱导训练免疫。我们对 17 例计划接受 BCG 治疗的 NMIBC 患者进行了前瞻性观察队列研究，并在 1 年 BCG 维持治疗期间测量了 9 个时间点的训练免疫参数。测量外周血单核细胞的体外细胞因子产生、表观遗传修饰和单核细胞转录组的变化。通过调查两个较大的 BCG 治疗和非 BCG 治疗的 NMIBC 患者队列中呼吸道感染的频率，作为训练免疫的替代测量。对候选训练免疫基因的遗传变异进行基于基因的关联分析，并将其与 BCG 治疗后的无复发生存率和无进展生存率进行关联，以研究训练免疫与临床反应之间的假设联系。

结果

我们发现，膀胱内 BCG 治疗后 6-12 周，循环单核细胞经异源体外刺激后 TNF 和 IL-1β 的产生增加，表明膀胱内 BCG 确实诱导了训练免疫；与非 BCG 治疗的 NMIBC 患者相比，BCG 治疗的患者发生呼吸道感染的风险降低了 37%（OR 0.63（95%CI 0.40 至 1.01））。结合染色质免疫沉淀测序和 RNA 测序与体外训练免疫实验的表观基因组学方法发现，BCG 治疗的个体中炎症小体活性增强。最后，影响训练免疫的基因的种系变异与 NMIBC 患者接受 BCG 治疗后的复发和进展相关。