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

头颈部鳞状细胞癌（HNSCC）是一种来自口腔、口咽部、喉部和下咽粘膜上皮的异质肿瘤（Economopoulou et al. 2016）。尽管HNSCC主要与吸烟和饮酒有关，但由于人乳头瘤病毒（HPV）感染而导致的口咽癌发病率也在增加（Fakhry C et al. 2008）。与HPV阴性的HNSCC患者相比，HPV相关的口咽部SCC患者对放化疗反应更好，3年总生存率更高（82.4%,vs. 57.1%） （Ang KK等，2010）。鉴于与HPV阴性HNSCC相关的不良预后，开发新的治疗策略以改善这些患者的生存结果至关重要。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。肿瘤相关巨噬细胞（tam）可以支持肿瘤生长，并与HNSCC患者预后不良相关（Balermpas et al. 2014）。放射治疗（RT）被用作HNSCC的主要和辅助治疗，通常与手术和化疗联合使用。RT诱导急性炎症反应，包括DNA损伤和STING/cGAS通路的激活。辐射的初始效应包括减轻肿瘤负担（Colton et al. 2020）。辐射的长期影响包括纤维化伤口愈合反应，可导致巨噬细胞的涌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为免疫抑制表型，从而支持肿瘤再生（Beach et al. 2022）。我们对当前免疫疗法（包括免疫检查点抑制剂和过继性免疫细胞疗法）的理解主要集中在对T细胞的影响上，然而越来越明显的是，TME的多个方面必须被靶向才能获得成功的抗肿瘤反应。tam可以阻止t细胞浸润到TME中，因此限制了这些治疗的有效性（Duan and Luo 2021）。以tam为目标是克服这一限制的潜在策略。可能的靶点包括抑制巨噬细胞募集到TME，诱导巨噬细胞向促炎抗肿瘤表型再极化，或抑制支持TAM功能的肿瘤。患者来源的类器官（PDOs）是三维原发肿瘤细胞培养物，保留了原始肿瘤的组织学和突变特征（Driehuis et al. 2019）。PDOs与患者单核/巨噬细胞共培养可以模拟tam -肿瘤相互作用和高通量药物筛选。目前pdo不能完全复制TME，长期将pdo与免疫细胞共培养仍然是一个挑战（Neal et al. 2018）。然而，pdo可以成为一种强大的工具，为体内小鼠模型提供RT/免疫治疗方案，并可能为个性化患者治疗提供信息。优化放射和免疫治疗组合，促进由肿瘤相关巨噬细胞驱动的抗肿瘤免疫反应

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