Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model
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Licun Wu1, Matthew Onn Wu1, Luis De la Maza1, Zhihong Yun1, Julie Yu1, Yidan Zhao1, John Cho2 and Marc de Perrot1
1 Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
2 Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
Marc de Perrot, email:
Keywords: mesothelioma, local radiotherapy, abscopal effect, immune checkpoint
Received: November 24, 2014 Accepted: February 03, 2015 Published: March 08, 2015
We previously demonstrated that blockade of immune suppressive CTLA-4 resulted in tumor growth delay when combined with chemotherapy in murine mesothelioma. Tumor-infiltrating T cells (TIT) after local radiotherapy (LRT) play critical roles in abscopal effect against cancer. We attempt to improve the local and abscopal effect by modulating T cell immunity with systemic blockade of CTLA-4 signal.The growth of primary tumors was significantly inhibited by LRT while CTLA-4 antibody enhanced the antitumor effect. Growth delay of the second tumors was achieved when the primary tumor was radiated. LRT resulted in more T cell infiltration into both tumors, including Treg and cytotoxic T cells. Interestingly, the proportion of Treg over effector T cells in both tumors was reversed after CTLA-4 blockade, while CD8 T cells were further activated. The expression of the immune-related genes was upregulated and cytokine production was significantly increased. LRT resulted in an increase of TIT, while CTLA-4 blockade led to significant reduction of Tregs and increase of cytotoxic T cells in both tumors. The abscopal effect is enhanced by targeting the immune checkpoints through modulation of T cell immune response in murine mesothelioma.
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