Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model

// Licun Wu 1 , Matthew Onn Wu 1 , Luis De la Maza 1 , Zhihong Yun 1 , Julie Yu 1 , Yidan Zhao 1 , John Cho 2 and Marc de Perrot 1 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 Correspondence to: Marc de Perrot, email: // Keywords : mesothelioma, local radiotherapy, abscopal effect, immune checkpoint Received : November 24, 2014 Accepted : February 03, 2015 Published : March 08, 2015 Abstract 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.