Role of macrophages in cancer immunotherapy: from patient multi-omic profiles to biological function

尽管免疫疗法引发了癌症治疗模式的转变，但许多患者未能反映出癌症与肿瘤微环境(TME)之间的动态相互作用。监测这种相互作用对于预测免疫治疗的反应是必不可少的。最近，Ciccarelli实验室对接受免疫治疗的结直肠癌进行了多组学研究，结果表明，反应性肿瘤的特征是干扰素-g途径的解除调控，以及参与PD1/PDL1介导的相互作用的T细胞和抗原提呈肿瘤相关巨噬细胞(TAMs)的大量渗透。TAMs在TME中的作用尚不清楚，但它们可能调节抗肿瘤免疫。利用自发的小鼠癌症模型，阿诺德实验室已经确定了干扰素调节的TAM，它可能与人类癌症中的TAM相似。这个翻译和跨学科的项目将进一步表征这个干扰素调节的/CD74+亚集(S)在小鼠和人类肿瘤微环境中的作用以及它们在免疫治疗反应中的作用。本项目将通过以下主要目标剖析CD74+TAMs的作用及其在抗肿瘤免疫反应中的作用：1)利用免疫疗法治疗的人胃肠癌和小鼠肿瘤的空间转录和成像质量细胞术来深入研究CD74+/干扰素调节的TAMs的表型，并在组织切片中表征它们与T细胞的相互作用。2)分析转录数据集，结合体内模型和体外培养技术，利用计算方法确定CD74+极化和肿瘤部位募集的候选介质，重点研究干扰素-γ作为关键候选极化分子的作用。3)在小鼠胃肠道肿瘤模型中，通过基因敲除和治疗干预，结合体外流式细胞术和共聚焦显微镜分析，从机制上解决TAMS与其调节T细胞反应的关系。将用于研究的关键研究方法将包括获得癌症基因组学、计算系统生物学、免疫学和体内癌症模型方面的专业知识。克洛伊将可以使用伦敦国王学院和克里克研究所的尖端计算和实验设施

Despite the paradigm shift in cancer treatment triggered by immunotherapy, many patients fail to respond reflecting the dynamic interplay between cancer and the tumour microenvironment (TME). Monitoring this interplay is imperative to predict response to immunotherapy. Recently, the Ciccarelli lab performed a multi-omic profile of immunotherapy-treated colorectal cancers showing that responsive tumours are characterised by deregulation of interferon-g pathways and rich infiltration of T cells and antigen-presenting tumour associated macrophages (TAMs), which engage in PD1/PDL1-mediated interactions1. The role of TAMs in the TME is unknown but they are likely to modulate anti-tumour immunity. Using spontaneous murine cancer models, the Arnold lab have identified interferon-regulated TAMs, which may be analogous to those in human cancer. This translational and inter-disciplinary project will further characterise the role of this interferon regulated/CD74+ TAM subset(s) in the tumour microenvironment of murine and human tumours and their role in the response to immunotherapy. This project will dissect the role of CD74+ TAMs and their role in the anti-tumour immune response through the following overarching project aims: 1) Employ spatial transcriptomics and imaging mass cytometry of immunotherapy-treated human gastrointestinal cancers and murine tumours to deeply phenotype (CD74+ /interferon-regulated TAMs and characterise their interactions with T cells in tissues sections. 2) Analyse transcriptomic datasets and employ computational approaches alongside in vivo models and in vitro culture techniques to identify candidate mediators of CD74+ TAM polarisation and recruitment at the tumour site, with a primary focus on studying the role of IFN-gamma as a key candidate polarisation molecule. 3) Mechanistically resolve the relationship between TAMs and their modulation of T cell responses via gene knockout and therapeutic intervention in murine models of gastrointestinal cancer alongside ex vivo flow cytometry and confocal microscopy analyses. Key research methods that will be used for the investigation will include gaining expertise in cancer genomics, computational systems biology, immunology and in vivo cancer models. Chloe will have access to cutting-edge computational and experimental facilities at both King's College London and Crick Institute