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M. Wu

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    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO20.09 - Systemic blockade of CTLA-4 signaling can improve the abscopal effect induced by local radiotherapy in a murine mesothelioma model (ID 651)

      10:30 - 12:00  |  Author(s): M. Wu

      • Abstract
      • Presentation
      • Slides

      Radiotherapy can induce direct cancer cell death and systemic anti-tumor immunity known as abscopal effect. For malignant pleural mesothelioma (MPM), postoperative hemithoracic radiation is important to control recurrence and metastasis for the resectable patients. We hypothesized that the abscopal effect also exists in malignant mesothelioma, and removal of the immunosuppressive checkpoints was able to enhance this effect induced by local radiotherapy.

      Murine malignant mesothelioma AB12 cells were injected subcutaneously into the right leg and flank of Balb/c mice either sequentially (primary/secondary tumors) or concurrently (local/distant tumors). Treatment was initiated on day 5 when primary (local) tumors were developed, and the immune-deficient NOD/SCID mice were used as controls. Local radiotherapy (LRT) with Gammacell-40 Irradiator was delivered to the tumor-bearing leg, whereas the rest of the body was protected with a lead chamber. CTLA-4 blockade with mAb was given 1 day after LRT. Tumor size was measured twice weekly to evaluate the anti-tumor effect. The immune responses, especially T cell activation in tumor, spleen and lymph node was determined by flow Cytometry. The expression of immune-related genes was quantified by RT-PCR, and tumor-infiltrating T cells were determined by immunofluorescent staining.

      The growth of primary tumors was significantly inhibited by LRT alone, and addition of anti-CTLA-4 mAb enhanced the antitumor effect. Interestingly, the secondary or distant tumors grew more slowly in mice whose primary tumor was treated with LRT than those untreated mice. Some secondary tumors were completely rejected when combined with anti-CTLA4 mAb. There was no such effect on the distant tumors in the immune deficient mice. Results demonstrated that LRT resulted in more T cell infiltration into both primary and secondary tumors. Tumor-infiltrating T cells had higher levels of ICOS and IFN-γ, and proliferated more rapidly after injection of irradiated AB12 cells. More activated CD4 and CD8 T cells were observed in the the draining lymph node (dLn) and spleen, and more dendritic cells trafficked to the dLn. The gene expression of cytolytic enzymes and cytokines was upregulated as well.

      LRT on primary tumors has abscopal effect on the secondary or distant tumor, and this effect can be enhanced by systemic blockade of CTLA-4 in murine mesothelioma. This approach might be translated into clinical trials for MPM patients.

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