Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Clin Cancer Res. 2023 Jun 1;29(11):2158-2169. doi: 10.1158/1078-0432.CCR-22-3918.
G-CSF enhances colon cancer development. This study defines the prevalence and effects of increased G-CSF signaling in human colon cancers and investigates G-CSF inhibition as an immunotherapeutic strategy against metastatic colon cancer.
Patient samples were used to evaluate G-CSF and G-CSF receptor (G-CSFR) levels by IHC with sera used to measure G-CSF levels. Peripheral blood mononuclear cells were used to assess the rate of G-CSFR+ T cells and IFNγ responses to chronic ex vivo G-CSF. An immunocompetent mouse model of peritoneal metastasis (MC38 cells in C57Bl/6J) was used to determine the effects of G-CSF inhibition (αG-CSF) on survival and the tumor microenvironment (TME) with flow and mass cytometry.
In human colon cancer samples, the levels of G-CSF and G-CSFR are higher compared to normal colon tissues from the same patient. High patient serum G-CSF is associated with increases in markers of poor prognosis, (e.g., VEGF, IL6). Circulating T cells from patients express G-CSFR at double the rate of T cells from controls. Prolonged G-CSF exposure decreases T cell IFNγ production. Treatment with αG-CSF shifts both the adaptive and innate compartments of the TME and increases survival (HR, 0.46; P = 0.0237) and tumor T-cell infiltration, activity, and IFNγ response with greater effects in female mice. There is a negative correlation between serum G-CSF levels and tumor-infiltrating T cells in patient samples from women.
These findings support G-CSF as an immunotherapeutic target against colon cancer with greater potential benefit in women.
G-CSF 增强结肠癌的发展。本研究定义了人结肠癌中增加的 G-CSF 信号的流行率和影响，并研究了 G-CSF 抑制作为一种针对转移性结肠癌的免疫治疗策略。
使用患者样本通过免疫组化（IHC）评估 G-CSF 和 G-CSF 受体（G-CSFR）水平，并使用血清测量 G-CSF 水平。使用外周血单核细胞评估慢性体外 G-CSF 刺激后 G-CSFR+T 细胞和 IFNγ反应的速度。使用免疫功能正常的腹膜转移小鼠模型（C57Bl/6J 中的 MC38 细胞）来确定 G-CSF 抑制（αG-CSF）对生存和肿瘤微环境（TME）的影响，方法是使用流式细胞术和液质联用技术。
在人结肠癌样本中，G-CSF 和 G-CSFR 的水平高于同一患者的正常结肠组织。患者血清中高水平的 G-CSF 与预后不良标志物（例如 VEGF、IL6）的增加相关。来自患者的循环 T 细胞表达 G-CSFR 的速率是对照 T 细胞的两倍。长期 G-CSF 暴露会降低 T 细胞 IFNγ 的产生。用 αG-CSF 治疗可改变 TME 的适应性和固有部分，并增加生存（HR，0.46；P = 0.0237）和肿瘤 T 细胞浸润、活性和 IFNγ 反应，对雌性小鼠的效果更大。在女性患者的样本中，血清 G-CSF 水平与肿瘤浸润性 T 细胞之间存在负相关。
这些发现支持 G-CSF 作为一种针对结肠癌的免疫治疗靶点，对女性患者具有更大的潜在益处。
