title: Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model.
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.
authors.affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Licun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Matthew Onn
authors.initials: MO
authors.lastname: Wu
authors.affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Luis
authors.initials: L
authors.lastname: De la Maza
authors.affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yun
authors.affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Yidan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Cho
authors.affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000528:radiation effects; D008654:Mesothelioma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010997:Pleural Neoplasms / Q000276:immunology* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011878:Radiotherapy / Q000379:methods; D013601:T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen
keywords: abscopal effect; immune checkpoint; local radiotherapy; mesothelioma