Significant technological advances in radiotherapy have been made in the past few decades. High-precision radiotherapy has recently become popular and is contributing to improvements in the local control of the irradiated target lesions and the reduction of adverse effects. Accordingly, for long-term survival, the importance of systemic cancer control, including at non-irradiated sites, is growing. Toward this challenge, the treatment methods in which anti-PD-1/PD-L1 antibodies that exert systemic effects by restoring anti-tumour immunity are combined with radiotherapy has attracted attention in recent years. Previous studies have reported the activation of anti-tumour immunity by radiotherapy, which simultaneously elevates PD-L1 expression, suggesting a potential for combination therapy. Radiotherapy induces so-called ‘immunogenic cell death’, which involves cell surface translocation of calreticulin and extracellular release of high-mobility group protein box 1 (HMGB-1) and adenosine-5′-triphosphate (ATP). Furthermore, radiotherapy causes immune activation via MHC class I upregulation and cGAS–STING pathway. In contrast, induction of immunosuppressive lymphocytes and the release of immunosuppressive cytokines and chemokines by radiotherapy contribute to immunosuppressive reactions. In this article, we review immune responses induced by radiotherapy as well as previous reports to support the rationale of combination of radiotherapy and anti-PD-1/PD-L1 antibodies. A number of preclinical and clinical studies have shown the efficacy of radiotherapy combined with immune checkpoint inhibition, hence combination therapy is considered to be an important future strategy for cancer treatment.

With the development of immune checkpoint inhibitors, the efficacy of immunotherapy as a cancer treatment that is effective against multiple tumor types has been established, and this modality came to be considered as the fourth pillar of cancer therapy. The clinical success of immunotherapy greatly changed the field of oncology by highlighting the importance of the immune system in cancer control and elimination. It has now become clear that research into, and the clinical application of, the immune response are important for effective cancer treatment. Moreover, it has become apparent that conventional cancer treatments, such as radiotherapy and chemotherapy, can modulate the cross-talk between the tumor and the immune system, and their efficacy depends, in part, on the ability to elicit antitumor immune response. The ability of radiotherapy to induce an immune response has become relevant in the immunotherapy age. Radiotherapy has been redefined as a partner for cancer immunotherapy, based on evidence indicating the potential synergistic effect of the combination of these therapeutic modalities. This review outlines the major findings reported to date on the immune response induced by radiotherapy and discusses the role of radiotherapy in combination with immunotherapy. Furthermore, we introduce research aimed at the clinical application of combination therapy and discuss its potential in clinical practice and future issues.

The reliability of DeepL Translator (DeepL GmbH, Cologne, Germany) for the translation for medical articles has not been verified yet. In this study, we investigated the accuracy of machine translation from Japanese to English for a medical article using the DeepL Translator. The subject of this study was an English-language medical article translated from Japanese, which had already been published. The original Japanese manuscript was translated into English using DeepL Translator. The translated English article was then back-translated into Japanese by three researchers. In turn, three other researchers compared the back-translated Japanese sentences with the original Japanese manuscript and calculated the percentage of sentences that retained the intended meaning. The mean ± standard deviation of the match rate for the entire article was 94.0 ± 2.9%. The match rate in the Results section was significantly higher than that in the other sections; while the match rate in the Materials and Methods section was significantly lower than the rate in the other sections. Compound sentences and sentences with an unclear subject and predicate appeared to be significant predictors for mismatched translation. The translation for a medical article from Japanese to English was performed accurately by DeepL Translator.

Cancer therapy using immune checkpoint inhibitors (ICIs) is a promising clinical strategy for patients with multiple types of cancer. The expression of programmed cell death ligand-1 (PD-L1), an immune-suppressor ligand, in cancer cells is a factor that influences the efficacy of ICI therapy, particularly in the anti-programmed cell death protein-1 (PD-1)/PD-L1 antibody therapy. PD-L1 expression in cancer cells are associated with tumor mutation burden including microsatellite instability because the accumulation of mutations in the cancer genome can produce abnormal proteins via mutant mRNAs, resulting in neoantigen production and HLA-neoantigen complex presentation in cancer cells. HLA-neoantigen presentation promotes immune activity within tumor environment; therefore, known as hot tumor. Thus, as the fidelity of DNA repair affects the generation of genomic mutations, the status of DNA repair and signaling in cancer cells can be considered prior to ICI therapy. The Cancer Genome Atlas (TCGA) and The Cancer Immunome Atlas (TCIA) database analysis showed that tumor samples harboring mutations in any non-homologous end joining, homologous recombination, or DNA damage signaling genes exhibit high neoantigen levels. Alternatively, an urgent task is to understand how the DNA damage-associated cancer treatments change the status of immune activity in patients because multiple clinical trials on combination therapy are ongoing. Recent studies demonstrated that multiple pathways regulate PD-L1 expression in cancer cells. Here, we summarize the regulation of the immune response to ICI therapy, including PD-L1 expression, and also discuss the potential strategies to improve the efficacy of ICI therapy for poor responders from the viewpoint of DNA damage response before or after DNA damage-associated cancer treatment.

Radiotherapy induces an immune response in the cancer microenvironment that may influence clinical outcome. The present study aimed to analyse the alteration of CD8⁺ T‑cell infiltration and programmed death‑ligand 1 (PD‑L1) expression following radiotherapy in clinical samples from patients with uterine cervical squamous cell carcinoma. Additionally, the current study sought to analyse the association between these immune responses and clinical outcomes. A total of 75 patients who received either definitive chemoradiotherapy or radiotherapy were retrospectively analyzed. CD8⁺ T‑cell infiltration and PD‑L1 expression were determined by immunohistochemistry using biopsy specimens before radiotherapy (pre‑RT) and after 10 Gy radiotherapy (post‑10 Gy). The PD‑L1⁺ rate was significantly increased from 5% (4/75) pre‑RT to 52% (39/75) post‑10 Gy (P<0.01). Despite this increase in the PD‑L1⁺ rate post‑10 Gy, there was no significant association between both pre‑RT and post‑10 Gy and overall survival (OS), locoregional control (LC) and progression‑free survival (PFS). On the other hand, the CD8⁺ T‑cell infiltration density was significantly decreased for all patients (median, 23.1% pre‑RT vs. 16.9% post‑10 Gy; P=0.038); however, this tended to increase in patients treated with radiotherapy alone (median, 17.7% pre‑RT vs. 24.0% post‑10 Gy; P=0.400). Notably, patients with high CD8⁺ T‑cell infiltration either pre‑RT or post‑10 Gy exhibited positive associations with OS, LC and PFS. Thus, the present analysis suggested that CD8⁺ T‑cell infiltration may be a prognostic biomarker for patients with cervical cancer receiving radiotherapy. Furthermore, immune checkpoint inhibitors may be effective in patients who have received radiotherapy, since radiotherapy upregulated PD‑L1 expression in cervical cancer specimens.