Abstract 3451: Lack of CD47 in the tumor microenvironment enhances anti-tumor adaptive immune responses when combined with ionizing radiation

Abstract

Abstract Over half of the new cancer patients diagnosed this year in the United States will require ionizing radiation (IR) therapy as part of their course of treatment. Achieving a curative response, however, is limited by detrimental side effects and off-target toxicities of IR to normal cells. We previously demonstrated that CD47 null mice or blockade of CD47 confers radioprotection to normal tissues including radiosensitive hematopoietic progenitors. On the other hand, blockade of CD47 enhanced the radiation-induced tumor growth delay in two syngenic mouse models. One possible explanation for this observation is that, by protecting tumor-associated immune cells, CD47 suppression increases tumor immune surveillance. To examine the role of T cell immunity, we used the F15-12 RM mouse fibrosarcoma model in athymic mice. Blockade of CD47 in combination with IR did not alter tumor growth in these T-cell deficient mice versus IR alone. However, adoptive transfer of CD8+ T-cells in combination with CD47 blockade and IR significantly enhanced the reduction in tumor growth when compared to tumors of mice irradiated in combination with the T cell transfer alone (186 ± 50 vs. 370 ± 123 mm3 respectively, N=8). In vitro experiments showed that blockade of CD47 enhances antigen dependent CD8+ mediated cytotoxicity of tumor cells. Furthermore, in a syngeneic tumor model of B16 melanoma we observed over a 50% reduction in volume of irradiated tumors in a CD47-/- host versus a WT host. Immunohistochemical staining indicated an increase of intratumoral CD8+ cytotoxic T-cells. Further analysis indicated that lack or blockade of CD47 in combination with IR resulted in a significant increase in granzyme B expression, further indicating that the increased target cell death may be mediated by this pathway. CD47 suppression may also reduce tumor growth by altering the immunosuppressive factor VEGF. In both tumor models, either blockade of or lack of CD47 in combination with IR was associated with a reduction in VEGF. VEGF is a potent pro-angiogenic factor and a potent immunosuppressive factor that inhibits activation of cytotoxic T-cells. Our findings indicate that agents targeting CD47 enhance anti-tumor T cell immunity when combined with radiation. Combining CD47 suppression with IR and adoptive T cell transfer may increase the percentage of curative responses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3451. doi:1538-7445.AM2012-3451