Modulation of the adaptive immune compartment by stromal fibroblasts

该项目将专注于更好地理解基质成纤维细胞与适应性免疫系统之间的相互作用，并将利用模型系统来研究具有亲或抗炎表型的成纤维细胞如何在免疫能力小鼠中对乳腺肿瘤生长的免疫反应进行差异调节。在临床上，乳腺癌对CTLA-4和PD-1抗体等免疫检查点分子抑制剂有很大的难耐性，这表明基质微环境具有高度的免疫抑制作用。一个可能的原因是，尽管细胞毒性CD8+ T细胞的浸润是乳腺癌的一个很好的预后指标，但很大一部分肿瘤显示T细胞募集不足或T细胞向II型肿瘤支持表型极化。越来越多的证据表明，癌症相关成纤维细胞（CAFs）在这些过程中起着关键作用。首先，相当大比例的乳腺肿瘤具有高成纤维细胞含量和相关的细胞外基质成分沉积，可为白细胞浸润创造屏障。其次，癌症研究所（ICR）的Isacke实验室和MedImmune的工作支持了caf的直接免疫调节作用。特别是，Isacke实验室有强有力的初步数据证明（a)直接从非侵袭性但不相关的侵袭性小鼠肿瘤中分离出的CAFs具有与适应性免疫系统激活相关的基因表达特征，并且(b)这与非侵袭性肿瘤相关i）具有更高的CD8+/CD4+ T细胞比率，ii)显示浸润T细胞向1型抗肿瘤表型极化。iii)与侵袭性肿瘤不同，在缺乏完整免疫系统的免疫受损小鼠中，与同基因Balb/c小鼠相比，肿瘤生长速度要快得多。利用MedImmune现有的资源（例如，额外的免疫能力小鼠模型，高水平的免疫学和生物信息学专业知识，针对各种免疫调节蛋白开发的新型抗体），BBSRC CASE学生将建立在这些初步数据的基础上，并通过跨两个地点的工作，利用这些模型任意表征caf介导的免疫抑制/激活模型。确定与不同CAF群体相关的基因表达变化，改变其调节适应性免疫室的能力，并建立免疫抑制型与免疫刺激型CAF中表达的差异调节基因的特征，确定介导CAF-适应性免疫细胞相互作用的关键成分，并利用生物信息学探索这些在其他疾病背景下的相关性，例如伤口愈合，在不同的临床前模型中，使用抗体刺激/抑制这些途径，确定这些成分如何与其他关键的免疫信号通路相互作用。该项目的目标将是确定(a)间质成纤维细胞调节疾病中抑制和促进适应性免疫平衡的机制，以及(b)这些cafc介导的作用如何与其他已知的免疫调节途径相互作用。例如使用PD-1/PD-L1抗体阻断免疫检查点。

This project will focus on better understanding the interactions between stromal fibroblasts and the adaptive immune system and will utilise model systems to investigate how fibroblasts with pro or anti-inflammatory phenotypes differentially regulate immune responses to breast tumours grown in immune competent mice. Clinically, breast cancers are largely refractory to inhibitors of immune checkpoint molecules such as CTLA-4 and PD-1 antibodies, suggesting that the stromal microenvironment is highly immune suppressive. A likely reason for this is that although infiltration of cytotoxic CD8+ T cells is a good prognostic indicator in breast cancers, a large proportion of tumours show poor T cell recruitment or polarisation of the T cells towards a type II tumour supportive phenotype. There is increasing evidence that cancer-associated fibroblasts (CAFs) play a key role in these processes. First, a significant proportion of breast tumours have a high fibroblast content and associated deposition of extracellular matrix components that can create a barrier for leucocyte infiltration. Second, work in both the Isacke laboratory at the Institute of Cancer Research (ICR) and at MedImmune support a direct immunomodulatory role for CAFs. In particular the Isacke laboratory has strong preliminary data demonstrating (a) that CAFs directly isolated from non-aggressive, but not related aggressive, mouse tumours have a gene expression signature associated with activation of the adaptive immune system, and (b) that this correlates with the non-aggressive tumours i) having a higher CD8+/CD4+ T cell ratio, ii) showing polarisation of the infiltrating T cells towards a type 1 anti-tumour phenotype, and iii) unlike the aggressive tumours, growing much more rapidly in immunocompromised mice in the absence of an intact immune system compared to syngeneic Balb/c mice. Using the resources available at MedImmune (e.g. additional immunocompetent mouse models, high level immunology and bioinformatics expertise, novel antibodies developed to various immune modulatory proteins), this BBSRC CASE studentship will build on this preliminary data and by working across both sites willfully characterise models of CAF-mediated immune suppression/activationusing these models, determine the gene expression changes associated with different CAF populations altered in their ability to modulate the adaptive immune compartment and build a signature of differentially regulated genes expressed in CAFs with immune-suppressive vs. immune-stimulatory phenotypes identify key components mediating CAF-adaptive immune cell interactions and explore using bioinformatics the relevance of these in other disease contexts e.g. wound healing, inflammatory disordersidentify how these components interact with other key immune signalling pathways using antibodies to stimulate/inhibit these pathways in the different preclinical models The objectives of this project will be to determine (a) the mechanism by which stromal fibroblasts modulate the balance of suppression and promotion of adaptive immunity in disease, and (b) how these CAF-mediated effects interact with other known immunomodulatory pathways, for example immune checkpoint blockade using PD-1/PD-L1 antibodies.