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.
Highlights
Malignant pleural mesothelioma (MPM) usually spreads locally along the ipsilateral pleura and distant metastasis is typically seen at the advanced stages [1]
We studied the abscopal effect induced by local radiotherapy (LRT) with γ-ray irradiation in murine mesothelioma model and determine if this effect could be promoted by removing the immunosuppressive Cyototoxic T lymphocyte-associated antigen-4 (CTLA-4) signal
LRT resulted in growth delay of both primary and secondary tumors, and addition of CTLA-4 blockade enhanced the antitumor effect
Summary
Malignant pleural mesothelioma (MPM) usually spreads locally along the ipsilateral pleura and distant metastasis is typically seen at the advanced stages [1]. Radical surgery and hemithoracic high dose radiation have shown encouraging results and is employed as primary forms of treatment in some cancers [2,3,4]. Even after receiving the radical surgery, MPM almost always recurs and/or metastasizes to the counterlateral chest or abdomen, resulting in poor prognosis [3,4]. Combinations of chemotherapy, surgery, and radiation therapy were initiated as a new treatment strategy to improve prognosis [5]. Advances in radiation technique have allowed the administration of high dose hemithoracic radiation therapy before or after surgery [6]. The ideal timing of chemotherapy relative to surgery and the role of intracavitary chemotherapy continue to be controversial issues [7]
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