Abstract：
BACKGROUND: Cancer immunotherapy aims to unleash the immune system\'s potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC.
METHODS: The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination was assessed using the YTN16 peritoneal dissemination tumor model. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A Janus kinase inhibitor (JAKi) was introduced based on the pathway analysis results.
RESULTS: Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8 + T cells. However, in mice resistant to dual ICI treatment, even with CD8 + T cell infiltration, most of the T cells exhibited an exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8 + T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment.
CONCLUSIONS: Dual ICI treatment exerts its anti-tumor effects by increasing tumor-specific CD8 + T cell infiltration, and the addition of JAKi further improves ICI resistance by reshaping the immunosuppressive TME.
METHODS: The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination was assessed using the YTN16 peritoneal dissemination tumor model. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A Janus kinase inhibitor (JAKi) was introduced based on the pathway analysis results.
RESULTS: Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8 + T cells. However, in mice resistant to dual ICI treatment, even with CD8 + T cell infiltration, most of the T cells exhibited an exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8 + T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment.
CONCLUSIONS: Dual ICI treatment exerts its anti-tumor effects by increasing tumor-specific CD8 + T cell infiltration, and the addition of JAKi further improves ICI resistance by reshaping the immunosuppressive TME.
摘要：
背景：癌症免疫疗法旨在释放免疫系统对抗癌细胞的潜能，为对免疫检查点抑制剂（ICIs）有反应的肿瘤提供持续缓解。虽然在胃癌（GC）试验中很有前途，在腹膜播散的情况下，ICI的疗效降低。我们的目标是确定策略，以增强ICI治疗的影响，特别是对于涉及GC腹膜传播的病例。
方法：抗PD1、CTLA4单独治疗的疗效，或组合使用YTN16腹膜播散肿瘤模型进行评估。收集腹膜和腹膜渗出物细胞用于后续分析。免疫组织化学染色,流式细胞术,进行了大量RNA序列分析以评估肿瘤微环境(TME)。基于途径分析结果,引入Janus激酶抑制剂(JAKi)。
结果：抗PD1和抗CTLA4联合治疗（双重ICI治疗）在某些小鼠中显示出治疗功效，主要由CD8+T细胞介导。然而,在对双重ICI治疗有抗性的小鼠中，即使有CD8+T细胞浸润，大多数T细胞表现出耗尽表型。值得注意的是,与未治疗组相比，耐药肿瘤显示Janus激酶-信号转导和转录激活因子（JAK-STAT）途径的异常激活，观察到巨噬细胞的浸润，中性粒细胞，和TME中的Tregs。JAKi的同时给药挽救了CD8+T细胞功能并重塑了免疫抑制性TME，导致双重ICI治疗的疗效增强。
结论：双重ICI治疗通过增加肿瘤特异性CD8+T细胞浸润发挥其抗肿瘤作用，JAKi的加入通过重塑免疫抑制TME进一步改善了ICI抗性。
方法：抗PD1、CTLA4单独治疗的疗效，或组合使用YTN16腹膜播散肿瘤模型进行评估。收集腹膜和腹膜渗出物细胞用于后续分析。免疫组织化学染色,流式细胞术,进行了大量RNA序列分析以评估肿瘤微环境(TME)。基于途径分析结果,引入Janus激酶抑制剂(JAKi)。
结果：抗PD1和抗CTLA4联合治疗（双重ICI治疗）在某些小鼠中显示出治疗功效，主要由CD8+T细胞介导。然而,在对双重ICI治疗有抗性的小鼠中，即使有CD8+T细胞浸润，大多数T细胞表现出耗尽表型。值得注意的是,与未治疗组相比，耐药肿瘤显示Janus激酶-信号转导和转录激活因子（JAK-STAT）途径的异常激活，观察到巨噬细胞的浸润，中性粒细胞，和TME中的Tregs。JAKi的同时给药挽救了CD8+T细胞功能并重塑了免疫抑制性TME，导致双重ICI治疗的疗效增强。
结论：双重ICI治疗通过增加肿瘤特异性CD8+T细胞浸润发挥其抗肿瘤作用，JAKi的加入通过重塑免疫抑制TME进一步改善了ICI抗性。
