Radiation-induced PD-L1 expression in tumor and its microenvironment facilitates cancer-immune escape: a narrative review

Abstract

Background and Objective: Radiotherapy (RT) is one of the fundamental anti-cancer regimens by means of inducing in situ tumor vaccination and driving a systemic anti-tumor immune response. It can affect the tumor microenvironment (TME) components consisting of blood vessels, immunocytes, fibroblasts, and extracellular matrix (ECM), and might subsequently suppress anti-tumor immunity through expression of molecules such as programmed death ligand-1 (PD-L1). Immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD-1)/PD-L1 therapies, have been regarded as effective in the reinvigoration of the immune system and another major cancer treatment. Experimentally, combination of RT and ICIs therapy shows a greater synergistic effect than either therapy alone.Methods: We performed a narrative review of the literature in the PubMed database. The research string comprised various combinations of "radiotherapy", "programmed death-ligand 1", "microenvironment", "exosome", "myeloid cell", "tumor cell", "tumor immunity". The database was searched independently by two authors. A third reviewer mediated any discordance of the results of the two screeners.Key Content and Findings: RT upregulates PD-L1 expression in tumor cells, tumor-derived exosomes (TEXs), myeloid-derived suppressor cells (MDSCs), and macrophages. The signaling pathways correlated to PD-L1 expression in tumor cells include the DNA damage signaling pathway, epidermal growth factor receptor (EGFR) pathway, interferon gamma (IFN-γ) pathway, cGAS-STING pathway, and JAK/STATs pathway.Conclusions: PD-L1 upregulation post-RT is found not only in tumor cells but also in the TME and is one of the mechanisms of tumor evasion. Therefore, further studies are necessary to fully comprehend this biological process. Meanwhile, combination of therapies has been shown to be effective, and novel approaches are to be developed as adjuvant to RT and ICIs therapy.

Neoadjuvant radiotherapy in ER+, HER2+, and triple-negative -specific breast cancer based humanized tumor mice enhances anti-PD-L1 treatment efficacy

“…The intrinsic PD-L1 expression in surviving cells remained unaffected by irradiation across all cell lines ( Figure 1B ). This observation contradicts findings from other preclinical research, such as those conducted by Wang ( 36 ) or Deng and colleagues ( 16 ), who reported an increased PD-L1 expression upon irradiation in mouse mammary tumor models (BALB/c, C57BL/6). However, our data align with observations made in clinical settings ( 37 ).…”

Neoadjuvant Immunotherapy and Chemoradiation Followed by Esophagectomy for Esophageal Cancer

“…However, the data did not include a neoadjuvant treatment modality inclusive of radiotherapy. Emerging data on the cellular effects of radiotherapy in the treatment of solid tumors has demonstrated upregulation of PD-L1 receptor expression on tumor cells as well as within the tumor microenvironment 16 . This suggests that there may be a synergistic mechanism in terms of anti-tumor effect following a neoadjuvant chemoRT+I/O in esophageal cancer.…”

Radiotherapy and immunology

“…Shao and colleagues reported that IR (4 Gy) significantly increased the m 6 A levels in several colorectal cancer cells, probably due to the reduced m 6 A eraser ALKBH5 after IR ( Shao et al, 2023 ). A recent report noted that IR increases m 6 A reader YTHDF2 in MDSCs both in vitro (4 Gy) and in vivo (one dose of 20 Gy) ( Wang et al, 2022 , 2023a ). These data suggest that IR-mediated alterations in expression of m 6 A proteins may impact anti-tumor efficacy.…”

“…Increasing evidence has demonstrated that radiation induces an increase in expression of PD-L1 on tumor cells in multiple cancers including colon, head and neck, squamous cell carcinoma, breast cancer, nasopharyngeal carcinoma, prostate cancer, and glioma ( Chen et al, 2023b ; Ding et al, 2020 ; Dovedi et al, 2014 ; Oweida et al, 2017 ; Wu et al, 2016 ). Radiation induces PD-L1 expression in tumor cells via various pathways like DNA damage/ATM/STAT3/IRF3 axis, IFN-γ/JAK/STAT/PD-L1 pathway, cGAS-STING signaling, epidermal growth factor receptor (EGFR)/PI3K-AKT cascade, and the HIF-1α signaling ( Ding et al, 2021 ; Wang et al, 2022 ). Of note, other signaling pathways may be involved in the regulation of PD-L1 expression in tumors.…”