Targeting tumour-associated macrophages in the HNSCC TME using radiotherapy/immunotherapy combinations

使用放射疗法/免疫疗法组合靶向 HNSCC TME 中的肿瘤相关巨噬细胞

• 批准号: 2886760
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2886760
• 关键词: Targeting; tumour; associated; macrophages; HNSCC

Head and neck squamous cell carcinoma (HNSCC) are a heterogenous group of tumours derived from the mucosal epithelium in the oral cavity, oropharynx, larynx and hypopharynx (Economopoulou et al. 2016). Although HNSCC are mostly associated with smoking and alcohol intake, there has been an increasing incidence of oropharyngeal cancers attributed to human papillomavirus (HPV) infection (Fakhry C et al. 2008). Patients with HPV associated oropharygeal SCC respond better to chemoradiation and have a better 3-year rates of overall survival (82.4%, vs. 57.1%) compared to HPV negative HNSCC patients (Ang KK et al. 2010). In view of the poor prognosis associated with HPV negative HNSCC, development of new therapeutic strategies to improve the survival outcome for these patients is essential. Many immune cells including macrophages, T-cells, B-cells, and dendritic cells are present in the tumour microenvironment (TME). Tumour associated macrophages (TAMs) can support tumour growth, and are associated with poor patient outcomes in HNSCC (Balermpas et al. 2014). Radiotherapy (RT) is used as a primary and adjuvant therapy for HNSCC, often in combination with surgery and chemotherapy. RT induces an acute inflammatory response which includes DNA damage and activation of the STING/cGAS pathway. This initial effect of radiation includes a reduction in tumour burden (Colton et al. 2020). A longer term effect of radiation involves a fibrotic wound-healing response that can lead to an influx of macrophages and remodelling of the collagen matrix. An important aspect of this longer term response is that the chemokine milieu can polarise macrophages to an immunosuppressive phenotype that can support tumour regrowth (Beach et al. 2022). There is increasing interest in modulating immune cells in combination with RT. Our understanding of current immunotherapies including immune checkpoint inhibitors and adoptive immune cell therapies is focused on the effect on T cells however it is becoming apparent that multiple aspects of the TME must be targeted to have a successful anti-tumour response. TAMs can prevent infiltration of T-cells into the TME and therefore limit the effectiveness of these treatments (Duan and Luo 2021). Targeting TAMs is a potential strategy to overcome this limitation. Possible targets include suppression of macrophage recruitment to the TME, inducing macrophage repolarisation towards a pro-inflammatory anti-tumour phenotype, or inhibiting tumour supporting TAM functions. Patient-derived organoids (PDOs) are three-dimensional primary tumour cell cultures that retain the original tumour's histological and mutational features (Driehuis et al. 2019). Co-culture of PDOs with patient monocytes/macrophages allows modelling of TAM-tumour interactions and high-throughput drug screening. Currently PDOs cannot fully replicate the TME and co-culturing PDOs with immune cells long-term remains a challenge (Neal et al. 2018). However, PDOs can be a powerful tool to inform RT/immunotherapy treatment regimens for in vivo mouse models, and could potentially inform personalised patient treatments.Optimise radiation and immunotherapy combinations to promote an anti-tumour immune response driven by tumour-associated macrophages

头部和颈部鳞状细胞癌（HNSCC）是一种来自口腔粘膜上皮的异源肿瘤，口腔，口咽，喉和咽咽（Economapoulou etal。2016）。尽管HNSCC主要与吸烟和酒精摄入有关，但归因于人乳头瘤病毒（HPV）感染的口咽癌的发生率越来越高（Fakhry C等，2008）。与HPV阴性HNSCC患者相比，患有HPV相关的口咽SCC的患者对化学放疗的反应更好，总生存率（82.4％，57.1％）更好（AngKK等人，2010年）。鉴于与HPV阴性HNSCC相关的预后不良，因此开发了改善这些患者生存结果的新的治疗策略。肿瘤微环境（TME）中存在许多免疫细胞，包括巨噬细胞，T细胞，B细胞和树突状细胞。肿瘤相关的巨噬细胞（TAMS）可以支持肿瘤的生长，并且与HNSCC中患者的差不良结局有关（Balermpas等，2014）。放疗（RT）通常与手术和化学疗法结合使用，用作HNSCC的主要和辅助治疗。 RT诱导急性炎症反应，其中包括DNA损伤和刺激/CGAS途径的激活。辐射的最初影响包括减轻肿瘤负担（Colton等，2020）。辐射的长期影响涉及纤维化伤口愈合反应，这可能导致巨噬细胞的流入和胶原基质的重塑。这种长期反应的一个重要方面是，趋化因子环境可以使巨噬细胞极化，以支持可以支持肿瘤再生的免疫抑制表型（Beach等，2022）。与RT结合调节免疫细胞的兴趣增加。我们对包括免疫检查点抑制剂和继发性免疫细胞疗法在内的当前免疫疗法的理解集中在对T细胞的影响上，但是很明显，必须将TME的多个方面靶向具有成功的抗肿瘤反应。 TAM可以防止T细胞渗入TME，因此限制了这些处理的有效性（Duan和Luo 2021）。靶向TAM是克服这一局限性的潜在策略。可能的靶标包括抑制巨噬细胞募集到TME，从而诱导巨噬细胞重透化对促炎性抗肿瘤表型，或抑制支持TAM功能的肿瘤。患者衍生的类器官（PDOS）是三维原发性肿瘤细胞培养物，可保留原始肿瘤的组织学和突变特征（Driehuis等人，2019年）。 PDO与患者单核细胞/巨噬细胞的共同培养允许对TAM-Tumour相互作用和高通量药物筛查进行建模。目前，PDOS无法长期与免疫细胞的TME和共培养PDO完全复制（Neal等人，2018年）。但是，PDO可以是为体内小鼠模型提供通知RT/免疫疗法治疗方案的强大工具，并有可能为个性化的患者治疗提供信息。优化的放射线和免疫疗法组合可以促进由肿瘤相关巨噬细胞驱动的抗肿瘤免疫反应