CT-26 和结肠 26 同基因小鼠模型的肿瘤免疫分析揭示了抗 PD-1 反应的机制,BMC Cancer

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CT-26 和结肠 26 同基因小鼠模型的肿瘤免疫分析揭示了抗 PD-1 反应的机制
BMC Cancer ( IF 3.4 ) Pub Date : 2021-11-13 , DOI: 10.1186/s12885-021-08974-3
Yosuke Sato ₁ , Yu Fu _{1,

2} , Hong Liu _{1,

3} , Min Young Lee ₁ , Michael H Shaw ₁

Affiliation

免疫检查点阻断 (ICB) 疗法改变了癌症治疗的范式。然而，ICB 的抗肿瘤反应对许多患者来说是不够的，并且仅限于特定的肿瘤类型。尽管进行了许多临床前和临床研究以了解 ICB 的抗肿瘤功效机制，但其机制尚未完全清楚。利用临床前肿瘤模型是了解治疗反应机制的一种方法。为了描述 ICB 在临床前同基因肿瘤模型中的抗肿瘤活性机制，我们选择了两种基于体内筛选抗 PD-1 治疗敏感性的同基因小鼠结肠直肠癌模型。我们对这两种模型进行了肿瘤免疫分析，以确定抗 PD-1 反应的潜在机制。我们在 23 个同基因肿瘤模型中进行了抗 PD-1 治疗的体内筛选，发现 CT-26 和结肠 26 是源自 BALB/c 小鼠的小鼠结肠直肠癌，对抗 PD-1 显示出不同的敏感性。CT-26 肿瘤小鼠对抗 PD-1 抗体的敏感性高于结肠 26，而两种模型对抗 CTLA4 抗体的敏感性相似。免疫分析显示 CT-26 肿瘤组织比结肠 26 浸润了更多的免疫细胞。基因组/转录组分析强调 Wnt 通路是 CT-26 和结肠 26 之间的潜在差异之一，表明 Wnt 活性在结肠 26 中高于结肠 26 CT-26。. CT-26 和结肠 26 同基因肿瘤模型显示出对抗 PD-1 治疗不同的敏感性，尽管这两种肿瘤细胞都是来自 BALB/c 株的鼠结肠直肠癌细胞系。通过用综合分析方法表征肿瘤组织中的小鼠细胞系和肿瘤免疫背景，我们发现 CT-26 显示出比结肠 26 具有更多浸润免疫细胞的“热肿瘤”特征。进一步的通路分析使我们能够提出一个假设Wnt 通路可能是区分 CT-26 与结肠 26 模型的主要因素之一，并与抗 PD-1 反应有关。我们专注于具有相似遗传背景但对抗 PD-1 治疗敏感性不同的临床前肿瘤模型的方法将有助于说明抗 PD-1 反应的潜在机制并产生一个新概念以协同当前的抗 PD-1癌症患者的治疗方法。我们发现 CT-26 显示出比结肠 26 具有更多浸润免疫细胞的“热肿瘤”特征。进一步的通路分析使我们能够提出一个假设，即 Wnt 通路可能是区分 CT-26 与结肠 26 模型和链接到抗 PD-1 反应。我们专注于具有相似遗传背景但对抗 PD-1 治疗敏感性不同的临床前肿瘤模型的方法将有助于说明抗 PD-1 反应的潜在机制并产生一个新概念以协同当前的抗 PD-1癌症患者的治疗方法。我们发现 CT-26 显示出比结肠 26 具有更多浸润免疫细胞的“热肿瘤”特征。进一步的通路分析使我们能够提出一个假设，即 Wnt 通路可能是区分 CT-26 与结肠 26 模型和链接到抗 PD-1 反应。我们专注于具有相似遗传背景但对抗 PD-1 治疗敏感性不同的临床前肿瘤模型的方法将有助于说明抗 PD-1 反应的潜在机制并产生一个新概念以协同当前的抗 PD-1癌症患者的治疗方法。

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Tumor-immune profiling of CT-26 and Colon 26 syngeneic mouse models reveals mechanism of anti-PD-1 response

Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies. However, anti-tumor response of the ICB is insufficient for many patients and limited to specific tumor types. Despite many preclinical and clinical studies to understand the mechanism of anti-tumor efficacy of ICB, the mechanism is not completely understood. Harnessing preclinical tumor models is one way to understand the mechanism of treatment response. In order to delineate the mechanisms of anti-tumor activity of ICB in preclinical syngeneic tumor models, we selected two syngeneic murine colorectal cancer models based on in vivo screening for sensitivity with anti-PD-1 therapy. We performed tumor-immune profiling of the two models to identify the potential mechanism for anti-PD-1 response. We performed in vivo screening for anti-PD-1 therapy across 23 syngeneic tumor models and found that CT-26 and Colon 26, which are murine colorectal carcinoma derived from BALB/c mice, showed different sensitivity to anti-PD-1. CT-26 tumor mice were more sensitive to the anti-PD-1 antibody than Colon 26, while both models show similarly sensitivity to anti-CTLA4 antibody. Immune-profiling showed that CT-26 tumor tissue was infiltrated with more immune cells than Colon 26. Genomic/transcriptomic analyses highlighted thatWnt pathway was one of the potential differences between CT-26 and Colon 26, showing Wnt activity was higher in Colon 26 than CT-26. . CT-26 and Colon 26 syngeneic tumor models showed different sensitivity to anti-PD-1 therapy, although both tumor cells are murine colorectal carcinoma cell lines from BALB/c strain. By characterizing the mouse cells lines and tumor-immune context in the tumor tissues with comprehensive analysis approaches, we found that CT-26 showed “hot tumor” profile with more infiltrated immune cells than Colon 26. Further pathway analyses enable us to propose a hypothesis that Wnt pathway could be one of the major factors to differentiate CT-26 from Colon 26 model and link to anti-PD-1 response. Our approach to focus on preclinical tumor models with similar genetic background but different sensitivity to anti-PD-1 therapy would contribute to illustrating the potential mechanism of anti-PD-1 response and to generating a novel concept to synergize current anti-PD-1 therapies for cancer patients.

更新日期：2021-11-14

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