目的: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)在局部中危前列腺癌(PCa)患者中诱导的全身抗肿瘤免疫反应。
方法:在2021年2月至2022年6月之间,前瞻性收集30例局限性PCa患者治疗前后(第5、14和30天)的外周血样本。患者纳入标准为:国际泌尿外科病理学家学会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。使用流式细胞术确定淋巴细胞和骨髓免疫细胞亚群的频率和活化状态。通过干扰素-γ酶联免疫斑点测定(ELISpot)确定PCa特异性T细胞对前列腺酸性磷酸酶(PSAP)和癌症睾丸抗原(纽约食管鳞状细胞癌1[NY-ESO-1])的反应。使用重复测量的方差分析和双侧Student'st检验来比较随时间和治疗组之间的免疫应答。
结果:除了年龄(中位数为68岁[IRE]和62岁[RARP],P=0.01)。IRE诱导全身调节性T细胞的消耗(P=0.0001)和激活的细胞毒性T淋巴细胞抗原4(CTLA-4)+分化簇(CD)4+(P<0.001)和CD8+(P=0.032)T细胞同时增加,与减少全身性免疫抑制一致,允许效应T细胞激活,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名免疫有能力的患者中的4名中诱导PSAP和/或NY-ESO-1特异性T细胞应答的扩增。暂时增加的活化的骨髓来源的抑制细胞频率(P=0.047)与RARP后的短暂免疫抑制一致。
结论:不可逆电穿孔可诱导局部PCa患者的PCa特异性全身免疫反应,帮助肿瘤微环境转化为更免疫允许的状态。通过与CTLA-4检查点抑制相结合,可以进一步提高治疗效果。可能为高风险的局部或(寡)转移性疾病开辟新的协同治疗模式。
OBJECTIVE: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.