局部前列腺癌的不可逆电穿孔可下调免疫抑制并诱导全身抗肿瘤 T 细胞激活 - IRE-IMMUNO 研究。
Irreversible electroporation of localised prostate cancer downregulates immune suppression and induces systemic anti-tumour T-cell activation - IRE-IMMUNO study.
发表日期:2024 Aug 05
作者:
Bart Geboers, Matthijs J Scheltema, Jason Jung, Joyce Bakker, Florentine E F Timmer, Xanthe Cerutti, Athos Katelaris, Paul Doan, William Gondoputro, Alexandar Blazevski, Shikha Agrawal, Jayne Matthews, Anne-Maree Haynes, Tim Robertson, James E Thompson, Martijn R Meijerink, Susan J Clark, Tanja D de Gruijl, Phillip D Stricker
来源:
BJU INTERNATIONAL
摘要:
前瞻性比较不可逆电穿孔(IRE)和机器人辅助根治性前列腺切除术(RARP)在局限性中危前列腺癌(PCa)患者中诱导的全身抗肿瘤免疫反应。2021年2月至2022年6月,治疗前后(前瞻性收集 30 名局限性 PCa 患者(第 5、14 和 30 天)的外周血样本。患者纳入标准为:国际泌尿病理学家协会2-3级、临床癌症分期≤T2c、前列腺特异性抗原水平<20ng/mL)。患者接受 IRE (n = 20) 或 RARP (n = 10) 治疗。使用流式细胞术测定淋巴细胞和骨髓免疫细胞亚群的频率和激活状态。通过干扰素-γ 酶联免疫斑点测定 (ELISpot) 测定 PCa 特异性 T 细胞对前列腺酸性磷酸酶 (PSAP) 和癌睾丸抗原(纽约食管鳞状细胞癌 1 [NY-ESO-1])的反应。使用重复测量方差分析和双侧学生 t 检验来比较随时间推移和治疗队列之间的免疫反应。除年龄外,各队列之间的患者和肿瘤特征相似(中位数 68 岁 [IRE] 和 62 岁 [IRE])。 RARP],P = 0.01)。 IRE 诱导全身调节性 T 细胞耗竭 (P = 0.0001),并同时增加活化的细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 分化簇 (CD)4 (P < 0.001) 和 CD8 (P = 0.032) T细胞,与全身免疫抑制的减少一致,允许效应 T 细胞激活,在 IRE 后 14 天达到峰值。效果与肿瘤体积/消融大小呈正相关。因此,IRE 在 8 名具有免疫能力的患者中的 4 名中诱导了 PSAP 和/或 NY-ESO-1 特异性 T 细胞反应的扩大。激活的骨髓源性抑制细胞频率暂时增加 (P = 0.047) 与 RARP 后短暂的免疫抑制一致。不可逆电穿孔在局部 PCa 患者中诱导 PCa 特异性全身免疫反应,帮助肿瘤微环境转变为更免疫允许的状态。与 CTLA-4 检查点抑制相结合可能会进一步增强治疗效果,可能为高风险局部或(寡聚)转移性疾病开辟新的协同治疗范例。© 2024 作者。 BJU International 约翰·威利 (John Wiley) 出版
To prospectively compare systemic anti-tumour immune responses induced by irreversible electroporation (IRE) and robot-assisted radical prostatectomy (RARP) in patients with localised intermediate-risk prostate cancer (PCa).Between February 2021 and June 2022, before and after treatment (at 5, 14 and 30 days) peripheral blood samples of 30 patients with localised PCa were prospectively collected. Patient inclusion criteria were: International Society of Urological Pathologists Grade 2-3, clinical cancer stage ≤T2c, prostate-specific antigen level <20 ng/mL). Patients were treated with IRE (n = 20) or RARP (n = 10). Frequency and activation status of lymphocytic and myeloid immune cell subsets were determined using flow cytometry. PCa-specific T-cell responses to prostatic acid phosphatase (PSAP) and cancer testis antigen (New York oesophageal squamous cell carcinoma 1 [NY-ESO-1]) were determined by interferon-γ enzyme-linked immunospot assay (ELISpot). Repeated-measures analysis of variance and two-sided Student's t-tests were used to compare immune responses over time and between treatment cohorts.Patient and tumour characteristics were similar between the cohorts except for age (median 68 years [IRE] and 62 years [RARP], P = 0.01). IRE induced depletion of systemic regulatory T cells (P = 0.0001) and a simultaneous increase in activated cytotoxic T-lymphocyte antigen 4 (CTLA-4)+ cluster of differentiation (CD)4+ (P < 0.001) and CD8+ (P = 0.032) T cells, consistent with reduction of systemic immune suppression allowing for effector T-cell activation, peaking 14 days after IRE. Effects were positively correlated with tumour volume/ablation size. Accordingly, IRE induced expansion of PSAP and/or NY-ESO-1 specific T-cell responses in four of the eight immune competent patients. Temporarily increased activated myeloid derived suppressor cell frequencies (P = 0.047) were consistent with transient immunosuppression after RARP.Irreversible electroporation induces a PCa-specific systemic immune response in patients with localised PCa, aiding conversion of the tumour microenvironment into a more immune permissive state. Therapeutic efficacy might be further enhanced by combination with CTLA-4 checkpoint inhibition, potentially opening up a new synergistic treatment paradigm for high-risk localised or (oligo)metastatic disease.© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.