P1.06-03 Selective Depletion of Foxp3+ Regulatory T Cells After Local Radiotherapy Induces Abscopal Effects in Murine Malignant Mesothelioma

Abstract

Increasing evidence indicates that local radiotherapy (LRT) can invoke both local and systemic immune responses. Combining blockade of radiation-induced immunosuppressive responses with LRT may augment antitumor effects. Mice expressing a diphtheria toxin (DT) receptor under control of the Foxp3 locus (DEREG mice) allow conditional and efficient depletion of Foxp3+ regulatory T cell (Treg) by DT injection. This study aimed to elucidate the antitumor effect of selective depletion of Tregs combined with LRT in a murine malignant mesothelioma model. The infiltration of CD8+ T cells and Tregs was examined by flow cytometry at different time points after nonablative hypofractionated radiation (5 Gy x 3 days) in a murine mesothelioma model. AB12 murine mesothelioma cells were injected s.c. into syngeneic DEREG mice at two separate sites, defined as a “primary” site that was irradiated and a “secondary” site outside the radiation field. These mice were treated with LRT alone, DT injection alone, or a combination of LRT and DT injection. The proportion of CD8+ T cells and Tregs of total CD45+ cells in tumors were not different between radiated and untreated mice on day 2 and 5 after LRT. However, on day 7 and 12, both CD8+ T cells and Tregs in tumors significantly increased in mice treated with LRT compared with those without LRT. Selective Treg depletion by DT injection after LRT showed the best tumor growth delay in both primary and secondary tumor sites compared with LRT alone and DT injection alone. CD8+ T cells in spleen showed increased intracellular IFN-γ and Granzyme B production in mice treated with a combination of LRT and DT injection. Selective Treg depletion after LRT has the potential to evoke efficient local and systemic antitumor responses in murine mesothelioma. Our findings might have implications for future therapeutic strategies in mesothelioma patients.