Coupling of response biomarkers between tumour and peripheral blood in patients undergoing chemoimmunotherapy

Platinum-based chemotherapy in combination with anti-PD-L1 antibodies has shown promising results in mesothelioma. However, the immunological mechanisms underlying its efficacy are not well understood and there are no predictive biomarkers of clinical outcomes to guide treatment decisions. Here, we combine time-course RNA sequencing of peripheral blood mononuclear cells with pre-treatment tumour transcriptome data from the 54-patient cohort in the single arm phase II DREAM study. In peripheral blood, CD8 + T effector memory cells with stem-like properties are more abundant in responders at baseline, 3 weeks, and 6 weeks into therapy. These peripheral blood changes are linked to the transcriptional state of the tumour microenvironment. The identified immunological correlates are predictive of response and provide further evidence for the additive nature of the interaction between platinum-based chemotherapy and PD-L1 antibodies. Our study highlights the complex, but predictive interactions between the tumour and immune cells in peripheral blood during the response to chemoimmunotherapy. 55 pleural mesothelioma patients were recruited from 8 Australian sites as a part of the phase II DREAM study. Patients were treated with up to 6 cycles of chemo-immunotherapy that included 3-weekly cisplatin or carboplatin in combination with pemetrexed and durvalumab. Maintenance included 12 months of durvalumab on a 4-weekly basis. Peripheral blood samples were drawn at three timepoints. The first was taken at pretreatment baseline prior to dexamethasone pre-medication (timepoint 0, BL). The subsequent two samples were taken before the second (timepoint 1, C2D1) and third cycles (timepoint 2, C3D1) of chemoimmunotherapy treatment. Single cell TCRseq was performed on the peripheral blood samples.

铂类化疗联合抗PD-L1（anti-PD-L1）抗体治疗在间皮瘤（mesothelioma）中已展现出颇具前景的疗效，但该疗法起效的免疫学机制尚未完全阐明，且目前尚无可指导临床治疗决策的临床结局预测生物标志物。本研究结合了单臂II期DREAM研究中54例患者队列的外周血单个核细胞（peripheral blood mononuclear cells）时序RNA测序数据与治疗前肿瘤转录组（transcriptome）数据。在外周血中，具有干细胞样特性的CD8+效应记忆T细胞在治疗基线、治疗3周及6周的应答者体内丰度更高。这类外周血免疫细胞的变化与肿瘤微环境（tumour microenvironment）的转录状态密切相关。本研究鉴定出的免疫学相关性指标可预测治疗应答，同时为铂类化疗与PD-L1抗体的协同交互作用提供了进一步证据。本研究揭示了在化疗免疫治疗（chemoimmunotherapy）应答过程中，肿瘤与外周血免疫细胞之间存在复杂且具备预测价值的交互作用。本项II期DREAM研究共从澳大利亚8个研究中心招募了55例胸膜间皮瘤患者。患者接受至多6个周期的化疗免疫治疗，方案为每3周给予顺铂或卡铂联合培美曲塞与度伐利尤单抗。维持治疗阶段为每4周给药一次度伐利尤单抗，持续12个月。研究共采集三个时间点的外周血样本：首次采集于治疗前基线期，且在地塞米松预给药之前（时间点0，BL）；后两次采集分别于化疗免疫治疗第2周期（时间点1，C2D1）及第3周期（时间点2，C3D1）开始前。研究对外周血样本进行了单细胞T细胞受体测序（single cell TCRseq）。