Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, characterized by poor prognosis. Although immune checkpoint inhibitors (ICIs) such as anti-PD-L1 antibodies have demonstrated clinical success in various cancers, they do not elicit a response in GBM, as it is a cold tumor with low neoantigen load and T cell exhaustion. Photodynamic therapy (PDT) which uses light at an appropriate wavelength in combination with a photosensitizer to selectively destroy tumor cells, has recently gained attention for its potential to stimulate anti-tumor immune responses. Among available photosensitizers, 5-aminolevulinic acid (5-ALA) is clinically used in GBM surgery to visualize tumor margins and improve resection outcomes. Given its approved clinical use and surgical compatibility, 5-ALA-based PDT represents a promising strategy for integration into GBM treatment protocols. This study aimed to investigate whether 5-ALA-based PDT can enhance the efficacy of anti-PD-L1 therapy in GBM. In vitro, PD-L1 expression was evaluated in GL26 and U87 glioma cell lines as well as in patient-derived GBM cells. PD-L1 was expressed in some tumor cells while no PD-L1 expression was observed in others, indicating that the level of PD-L1 expression varies among glioblastomas. In the GL26 cell line, which initially exhibited low PD-L1 expression, treatment with 5-ALA PDT significantly increased PD-L1 expression. This suggests that the therapeutic efficacy of anti-PD-L1 treatment may be enhanced following 5-ALA PDT. In vivo, heterotopic (subcutaneous) and orthotopic GBM mouse models using the GL26 cells were established. Mice received 5-ALA PDT, anti-PD-L1, or a combination of both, and tumor growth, immune cell infiltration, and overall survival were evaluated. In the heterotopic (subcutaneous) model, GL26 cells was implanted into both flanks, with irradiation applied to the left side, designated as the primary tumor. The right side, which did not receive irradiation, was designated as the distant tumor. In this model, the combination of 5-ALA PDT and anti-PD-L1 treatment suppressed both primary and distant tumor growth, although the effect on distant tumors was not statistically significant. "Additionally, in the combination group, CD8+T call infiltration was elevated in primary and distant tumors. Apoptosis was most pronounced in the combination group. In the orthotopic model, combination treatment significantly improved survival. Furthermore CD8+T cells and NKT cells responses were observed in brain tumor-infiltrating lymphocytes (TILs). Thease results suggest that combining 5-ALA PDT with anti-PD-L1 therapy improves survival and boosts immune responses. While strong synergy was not always observed, an additive effect was seen, supporting the potential of this combination for GBM treatment".
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