Elimination of radiation‐induced senescent cancer cells and stromal cells in vitro by near‐infrared photoimmunotherapy

Abstract

Abstract Introduction Therapy‐induced senescent cancer and stromal cells secrete cytokines and growth factors to promote tumor progression. Therefore, senescent cells may be novel targets for tumor treatment. Near‐infrared photoimmunotherapy (NIR‐PIT) is a highly tumor‐selective therapy that employs conjugates of a molecular‐targeting antibody and photoabsorber. Thus, NIR‐PIT has the potential to be applied as a novel senolytic therapy. This study aims to investigate the efficacy of NIR‐PIT treatment on senescent cancer and stromal cells. Methods Two cancer cell lines (human lung adenocarcinoma A549 cells and human pancreatic cancer MIA PaCa‐2 cells) and two normal cell lines (mouse fibroblast transfected with human epidermal growth factor receptor 2 [HER2] cells and human fibroblast WI38 cells) were used. The cytotoxicity of NIR‐PIT was evaluated using anti‐epidermal growth factor receptor (EGFR) antibody panitumumab and anti‐HER2 antibody transtuzumab. Results Cellular senescence was induced in A549 and MIA PaCa‐2 cells by 10 Gy γ‐irradiation. The up‐regulation of cellular senescence markers and characteristic morphological changes in senescent cells, including enlargement, flattening, and multinucleation, were observed in cancer cells after 5 days of γ‐irradiation. Then, NIR‐PIT targeting EGFR was performed on these senescent cancer cells. The NIR‐PIT induced morphological changes, including bleb formation, swelling, and the inflow of extracellular fluid, and induced a significant decrease in cellular viability. These results suggested that NIR‐PIT may induce cytotoxicity using the same mechanism in senescent cancer cells. In addition, similar morphological changes were also induced in radiation‐induced senescent 3T3‐HER2 fibroblasts by NIR‐PIT targeting human epidermal growth factor receptor 2. Conclusion NIR‐PIT eliminates both senescent cancer and stromal cells in vitro suggesting it may be a novel strategy for tumor treatment.

Keywords

• molecular target therapy
• near‐infrared photoimmunotherapy
• senescent cells
• tumor stroma
• tumor treatment