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

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