Abstract
Rationale: The low response rate of immunotherapy, such as anti-PD-L1/PD-1 and anti-CTLA4, has limited its application to a wider population of cancer patients. One widely accepted view is that inflammation within the tumor microenvironment is low or ineffective for inducing the sufficient infiltration and/or activation of lymphocytes. Here, a highly tumor-selective anti-PD-L1 (αPD-L1) antibody was developed through PET imaging screening, and it was radiolabeled with Lu-177 for PD-L1-targeted radioimmunotherapy (RIT) and radiation-synergized immunotherapy. Methods: A series of αPD-L1 antibodies were radiolabeled with zirconium-89 for PET imaging to screen the most suitable antibodies for RIT. Mice were divided into an immunotherapy group, a RIT group and a radiation-synergized immunotherapy group to evaluate the therapeutic effect. Alterations in the tumor microenvironment after treatment were assessed using flow cytometry and immunofluorescence microscopy. Results: Radiation-synergistic RIT can achieve a significantly better therapeutic effect than immunotherapy or RIT alone. The dosages of the radiopharmaceuticals and αPD-L1 antibodies were reduced, the infiltration of CD4+ and CD8+ T cells in the tumor microenvironment was increased, and no side effects were observed. This radiation-synergistic RIT strategy successfully showed a strong synergistic effect with αPD-L1 checkpoint blockade therapy, at least in the mouse model. Conclusions: PET imaging of 89Zr-labeled antibodies is an effective method for antibody screening. RIT with a 177Lu-labeled αPD-L1 antibody could successfully upregulate antitumor immunity in the tumor microenvironment and turn "cold" tumors "hot" for immunotherapy.