Metabolites regulating macrophage function in colorectal cancer

摘要 大多数结直肠癌(CRC)患者由于T细胞缺乏而对免疫检查点抑制剂治疗无反应 细胞渗透和免疫抑制环境。结直肠癌的病理特征是独特的 肿瘤微环境中的复杂微生物群。不同的细菌种类和代谢物 肿瘤可以改变浸润性免疫细胞的活性和功能，调节肿瘤的免疫环境。 因此，了解富含肿瘤的代谢物如何改变免疫环境对 开发新的微生物区系/代谢物干预方法。 我们观察到类似于M2表型的巨噬细胞在结直肠癌样本中比例较高。 与患者匹配的正常组织相比。我们对结直肠癌组织的代谢分析显示， 与巨噬细胞表型改变密切相关的必需氨基酸。此外，单核细胞 暴露于色氨酸和苯丙氨酸等富含肿瘤的代谢物会增加与 免疫抑制的巨噬细胞。然而，微生物衍生的代谢物是否会改变巨噬细胞 极化和促进免疫抑制表型，这可以影响免疫环境 CRC，目前仍不清楚。我们推测，结直肠癌中代谢产物的变化与 免疫抑制巨噬细胞及其重要的肿瘤代谢产物对巨噬细胞的调节作用 表型。在目标1中，我们将评估肿瘤富集型代谢产物对巨噬细胞表型的影响。在……里面 目的2，我们将从功能上验证影响结直肠癌有机物中巨噬细胞极化的关键代谢物 同种文化模式。 我们将使用一种代谢物筛选方法，使用来自 健康捐赠者和结直肠癌患者评估肿瘤富集型代谢物是否可以促进 免疫抑制的巨噬细胞表型。此外，我们将使用人类微卫星稳定和 微卫星不稳定性结直肠癌有机物与患者匹配的未分化单核细胞和肿瘤- 浓缩代谢物以评估巨噬细胞亚型的变化。我们将确定关键的代谢物可以改变 巨噬细胞的表型和功能，有助于形成持续的免疫抑制肿瘤环境。 冲击力。确定肿瘤富集型代谢物和巨噬细胞表型之间的相互作用将增加 这项研究通过巩固免疫环境可以被操纵的前提而产生的临床意义 通过内源性代谢调节。

ABSTRACT Most colorectal cancer (CRC) patients do not respond to immune checkpoint inhibitor therapies due to poor T cell infiltration and an immune suppressive environment. The pathological characteristics of CRC are unique due to the complex microbiome in the tumor microenvironment. Diverse bacterial species and metabolites in the tumor can alter the activity and function of infiltrating immune cells, regulating the tumor's immune environment. Therefore, understanding how tumor-enriched metabolites change the immune environment is crucial for developing novel microbiota/metabolite intervention approaches. We observed that macrophages resembling an M2-like phenotype are in a higher proportion in CRC samples compared to patient-matched normal tissues. Our metabolomic analysis of CRC tissues showed increases in essential amino acids, which strongly correlate with altered macrophage phenotype. Further, monocytes exposed to tumor-enriched metabolites such as tryptophan and phenylalanine increase markers associated with immunosuppressive macrophages. However, whether microbial-derived metabolites alter macrophage polarization and contribute to immunosuppressive phenotypes, which can influence the immune environment in CRC, remains unknown. We hypothesize that altered enrichment of metabolites in CRC correlates with immunosuppressive macrophages and that critical tumor-enriched metabolites modulate the macrophage phenotypes. In Aim 1, we will assess the impact of tumor-enriched metabolites on macrophage phenotype. In Aim 2, we will functionally validate key metabolites influencing macrophage polarization in CRC organoid coculture models. We will use a metabolite screening approach using human primary peripheral blood mononuclear cells from healthy donors and CRC patients to assess whether tumor-enriched metabolites can promote immunosuppressive macrophage phenotypes. In addition, we will use human microsatellite stable and microsatellite instable CRC organoids cocultured with patients matched undifferentiated monocytes and tumor- enriched metabolites to assess shifts in macrophage subtypes. We will identify critical metabolites that can alter macrophage phenotype and function, contributing to a sustained immunosuppressive tumor environment. Impact. Determining interactions between tumor-enriched metabolites and macrophage phenotype will increase the clinical implications of this study by solidifying the premise that the immune environment can be manipulated by endogenous metabolic regulation.