Although immune checkpoint inhibitors (ICIs), such as the anti-programmed death-ligand 1 (PD-L1) antibody, have been developed for the treatment of canine malignant melanoma, desirable clinical efficacies have not been achieved. Recent studies in humans have suggested that radiation therapy (RT) combined with ICIs induces robust systemic antitumour immunity in patients with cancer. This study retrospectively examined the therapeutic efficacy of combination therapy (hypofractionated RT and anti-PD-L1 antibody [c4G12]) in dogs with pulmonary metastatic oral malignant melanoma. The intrathoracic clinical benefit rate (CBR)/median overall survival (OS) in the no RT (n = 20, free from the effect of RT), previous RT (n = 9, received RT ≤8 weeks prior to the first c4G12 dose), and concurrent RT (n = 10, c4G12 therapy within ±1 week of the first RT fraction) groups were 10%/185 days, 55.6%/283.5 days (p < 0.05 vs. no RT group), and 20%/129 days (p > 0.05 vs. no RT group), respectively. The adverse events were considered to be tolerable in the combination therapy. Thus, hypofractionated RT before the initiation of c4G12 therapy can be an effective approach for enhancing the therapeutic efficacy of immunotherapy, with acceptable safety profiles. Further prospective clinical studies are required to confirm the findings of this study.

Expression of programmed death ligand 1 (PD‐L1) on tumour cells provides an immune evasion mechanism by inducing suppression of cytotoxic T cells. Various regulatory mechanisms of PD‐L1 expression have been described in human tumours, however, little is known in canine tumours. To investigate whether inflammatory signalling is involved in PD‐L1 regulation in canine tumours, the effects of interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α treatment were examined in canine malignant melanoma cell lines (CMeC and LMeC) and an osteosarcoma cell line (HMPOS). The protein level of PD‐L1 expression was upregulated by IFN‐γ and TNF‐α stimulation. Upon IFN‐γ stimulation, all cell lines showed an increase in expression of PD‐L1, signal transducer and activator of transcription (STAT)1, STAT3 and genes regulated by STAT activation. Upregulated expression of these genes was suppressed by the addition of a JAK inhibitor, oclacitinib. Contrastingly, upon TNF‐α stimulation, all cell lines exhibited higher gene expression of the nuclear factor kappa B (NF‐κB) gene RELA and genes regulated by NF‐κB activation, whereas expression of PD‐L1 was upregulated in LMeC only. Upregulated expression of these genes was suppressed by the addition of an NF‐κB inhibitor, BAY 11‐7082. The expression level of cell surface PD‐L1 induced by IFN‐γ and TNF‐α treatment was reduced by oclacitinib and BAY 11‐7082, respectively, indicating that upregulation of PD‐L1 expression by IFN‐γ and TNF‐α stimulation is regulated via the JAK‐STAT and NF‐κB signalling pathways, respectively. These results provide insights into the role of inflammatory signalling in PD‐L1 regulation in canine tumours.

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