Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.
Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland.
Front Immunol. 2022 Jan 27;13:823225. doi: 10.3389/fimmu.2022.823225. eCollection 2022.
Immune checkpoint inhibitors (ICIs) are being investigated for their role as an adjunct in the multimodal treatment of esophageal adenocarcinoma (EAC). The most effective time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumor immunity perioperatively to help inform the optimal timing of ICIs into current standards of care for EAC patients.
Systemic immunity in 11 EAC patients was phenotyped immediately prior to esophagectomy (POD-0) and post-operatively (POD)-1, 3, 7 and week 6. Longitudinal serological profiling was conducted by ELISA. The frequency of circulating lymphocytes, activation status, immune checkpoint expression and damage-associated molecular patterns was assessed by flow cytometry.
The frequency of naïve T-cells significantly increased in circulation post-esophagectomy from POD-0 to POD-7 (p<0.01) with a significant decrease in effector memory T-cells by POD7 followed by a subsequent increase by week 6 (p<0.05). A significant increase in activated circulating CD27 T-cells was observed from POD-0 to POD-7 (p<0.05). The percentage of PD-1 and CTLA-4 T-cells peaked on POD-1 and was significantly decreased by week 6 (p<0.01). There was a significant increase in soluble PD-1, PD-L2, TIGIT and LAG-3 from POD-3 to week 6 (p<0.01). Increased checkpoint expression correlated with those who developed metastatic disease early in their postoperative course. Th1 cytokines and co-stimulatory factors decreased significantly in the immediate post-operative setting, with a reduction in IFN-γ, IL-12p40, IL-1RA, CD28, CD40L and TNF-α. A simultaneous increase was observed in Th2 cytokines in the immediate post-operative setting, with a significant increase in IL-4, IL-10, IL-16 and MCP-1 before returning to preoperative levels at week 6.
Our study highlights the prevailing Th2-like immunophenotype post-surgery. Therefore, shifting the balance in favour of a Th1-like phenotype would offer a potent therapeutic approach to promote cancer regression and prevent recurrence in the adjuvant setting and could potentially propagate anti-tumour immune responses perioperatively if administered in the immediate neoadjuvant setting. Consequently, this body of work paves the way for further studies and appropriate trial design is needed to further interrogate and validate the use of ICI in the multimodal treatment of locally advanced disease in the neoadjuvant and adjuvant setting.
免疫检查点抑制剂（ICIs）正在被研究作为食管腺癌（EAC）多模态治疗的辅助手段。将 ICI 纳入治疗的最佳时间仍不清楚。我们的研究对围手术期的全身抗肿瘤免疫进行了分析，以帮助为 EAC 患者提供当前治疗标准中 ICI 的最佳时机。
在 11 例 EAC 患者行食管切除术（POD-0）前和术后（POD）-1、3、7 和 6 周时，对其进行了系统免疫表型分析。通过 ELISA 进行了纵向血清学分析。通过流式细胞术评估循环淋巴细胞的频率、激活状态、免疫检查点表达和损伤相关分子模式。
与 POD-0 相比，手术后循环中幼稚 T 细胞的频率在 POD-7 时显著增加（p<0.01），效应记忆 T 细胞在 POD7 时显著减少，随后在 6 周时再次增加（p<0.05）。从 POD-0 到 POD-7，循环中激活的 CD27 T 细胞的百分比显著增加（p<0.05）。PD-1 和 CTLA-4 T 细胞的百分比在 POD-1 时达到峰值，在 6 周时显著降低（p<0.01）。从 POD-3 到 6 周时，可溶性 PD-1、PD-L2、TIGIT 和 LAG-3 显著增加（p<0.01）。检查点表达的增加与术后早期发生转移性疾病的患者有关。在术后即刻，Th1 细胞因子和共刺激因子显著减少，IFN-γ、IL-12p40、IL-1RA、CD28、CD40L 和 TNF-α减少。在术后即刻，Th2 细胞因子同时增加，IL-4、IL-10、IL-16 和 MCP-1 显著增加，6 周时恢复到术前水平。
我们的研究强调了手术后普遍存在的 Th2 样免疫表型。因此，有利于 Th1 样表型的转变将为促进癌症消退和预防辅助治疗中的复发提供有力的治疗方法，并且如果在新辅助治疗中即刻给药，可能会在围手术期促进抗肿瘤免疫反应。因此，这项工作为进一步的研究奠定了基础，需要适当的试验设计来进一步研究和验证 ICI 在新辅助和辅助局部晚期疾病多模态治疗中的应用。
