Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Medical Department, Amoy Diagnostics Co Ltd, Xiamen, Fujian, China.
J Immunother Cancer. 2024 Aug 28;12(8):e008942. doi: 10.1136/jitc-2024-008942.
Neoadjuvant chemoimmunotherapy has a promising effect on locally advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers robustly predicting therapeutic response are still lacking.
Formalin-fixed and paraffin-embedded pre-neoadjuvant chemoimmunotherapy biopsy samples from locally advanced ESCC patients were collected. Cohort 1 composed of 66 locally advanced ESCC patients from a prospective clinical trial (NCT04506138) received two cycles of camrelizumab in combination with nab-paclitaxel and carboplatin every 3 weeks. Cohort 2 included 48 patients receiving various types of immune checkpoint inhibitors with (nab-)paclitaxel and platinum-based chemotherapy as neoadjuvant therapy. Cohort 3 consisted of 27 ESCC patients receiving neoadjuvant treatment of toripalimab with chemotherapy and was used as the external validation dataset. Targeted RNA sequencing, immunohistochemistry for programmed death ligand 1 (PD-L1), and multiplex immunofluorescence (mIF) imaging were performed.
Integration of targeted RNA sequencing, PD-L1 immunohistochemistry, and mIF revealed a significant immune-suppressive microenvironment with higher neutrophil infiltration, enriched TGF-β, and cell cycle pathways in non-pathological complete response (non-pCR) patients. NK, activated CD4 T cell infiltration, interferon-gamma, antigen processing and presentation, and other immune response signatures were significantly associated with pCR. Based on discovered tumor microenvironmental characteristics and their closely related genes were screened. Consequently, a seven-gene neoadjuvant chemoimmunotherapy risk prediction signature (NCIRPs) model, was constructed. In addition to cohort 1, this model alone or with PD-L1-combined positive score (CPS) demonstrated a higher prediction accuracy of pathological response than PD-L1 CPS or other routinely used immune signatures, such as IFN-γ, in cohorts 2 and 3. Neither prognostic association nor correlation with response to chemoradiotherapy was observed in The Cancer Genome Atlas Program ESCC dataset or in ESCC patients in the neoadjuvant chemoradiotherapy cohort (cohort 4).
The NCIRPs model that was developed and validated using treatment-naïve endoscopic samples from the largest ESCC neoadjuvant chemoimmunotherapy dataset represents a robust and clinically meaningful approach to select a putative responder for neoadjuvant chemoimmunotherapy in locally advanced ESCC patients.
新辅助化疗免疫治疗对局部晚期食管鳞癌（ESCC）有显著疗效。然而，可靠的生物标志物能够预测治疗反应仍缺乏。
收集了局部晚期 ESCC 患者新辅助化疗免疫治疗前的福尔马林固定石蜡包埋活检样本。队列 1 由来自前瞻性临床试验（NCT04506138）的 66 名局部晚期 ESCC 患者组成，每 3 周接受两次卡瑞利珠单抗联合纳武利尤单抗和卡铂治疗。队列 2 包括 48 名接受各种类型免疫检查点抑制剂联合（纳武利尤单抗）紫杉醇和铂类化疗作为新辅助治疗的患者。队列 3 由 27 名接受特瑞普利单抗联合化疗新辅助治疗的 ESCC 患者组成，作为外部验证数据集。进行了靶向 RNA 测序、程序性死亡配体 1（PD-L1）免疫组化和多重免疫荧光（mIF）成像。
整合靶向 RNA 测序、PD-L1 免疫组化和 mIF 显示，非病理完全缓解（non-pCR）患者存在显著的免疫抑制微环境，中性粒细胞浸润增加，富含 TGF-β 和细胞周期途径。NK、活化 CD4 T 细胞浸润、干扰素-γ、抗原处理和呈递以及其他免疫反应特征与 pCR 显著相关。基于发现的肿瘤微环境特征及其密切相关的基因进行了筛选。随后，构建了一个七基因新辅助化疗免疫治疗风险预测标志（NCIRPs）模型。除了队列 1，该模型单独或与 PD-L1 联合阳性评分（CPS）在队列 2 和 3 中，与 PD-L1 CPS 或其他常规使用的免疫标志物（如 IFN-γ）相比，具有更高的病理反应预测准确性。在癌症基因组图谱计划 ESCC 数据集或新辅助放化疗队列（队列 4）的 ESCC 患者中，均未观察到与预后相关或与放化疗反应相关。
使用最大的 ESCC 新辅助化疗免疫治疗数据集的治疗前内镜样本开发和验证的 NCIRPs 模型，代表了一种可靠且具有临床意义的方法，可以选择局部晚期 ESCC 患者新辅助化疗免疫治疗的潜在应答者。
