Partial versus whole tumor-volume irradiation in combination with immunotherapy: Comparable outcomes in immunosuppressed mouse models of oral squamous cell carcinoma

Radiotherapy is a standard therapy for oral squamous cell carcinoma (OSCC) with immunomodulatory potential. Due to high lymphocyte radiosensitivity, partial tumor-volume irradiation (pIR), targeting only part of the tumor, is being explored for immunomodulation. This study compared the effects of whole tumor-volume irradiation (IR) and pIR, targeting approximately 50 % of the tumor volume, in combination with anti-PD-1 immune checkpoint inhibitors (ICI). The therapeutic efficacy of a single 15 Gy IR or pIR dose combined with anti-PD-1 ICI was evaluated in two immune cold murine OSCC models: human papillomavirus (HPV)-negative MOC1 and HPV-positive MOC1-HPV K1 stably expressing HPV-16 oncogenes E6/E7. Additionally, immune cell populations in the tumor microenvironment (TME) were analyzed using flow cytometry. Both IR and pIR induced transient immune cell infiltration in the TME. However, pIR led to significantly lower tumor growth inhibition than IR. While IR + ICI failed to improve survival compared to IR alone, pIR + ICI significantly prolonged survival compared to pIR alone in the MOC1 model, along with increase in cytotoxic T cell infiltration. In the MOC1-HPV K1 model, responses varied. Responding tumors were enriched with effector memory T cells, whereas non-responders exhibited increased neutrophil (MDSCs) and monocyte-derived dendritic cells infiltration. The study indicates that while pIR has immunomodulatory potential, its effects are comparable to IR in the tested settings. Further research is needed to optimize dosing and scheduling for pIR and anti-PD-1 ICI. Additionally, combination with other immunotherapies could be explored in further studies to enhance treatment efficacy in immune cold OSCC models.