Dual targeting of CTLA-4 and CD47 on Treg cells promotes immunity against solid tumors.

Targeting T_reg cells: Depletion of regulatory T (T_reg) cells is an attractive strategy to promote antitumor immunity. One strategy that could deplete T_reg cells is blockade of the "do not eat me" signal, CD47, which prevents T_reg cells from being targets of phagocytosis. However, CD47 is broadly expressed, making T_reg cell–specific targeting difficult. To selectively deplete T_reg cells, Zhang et al. designed a heterodimer that combines an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody, which targets intratumoral T_reg cells, and the CD47 ligand, signal regulatory protein α (SIRPα). Treatment with this heterodimer increased phagocytosis of T_reg cells, leading to their depletion, and promoted antitumor immunity in mouse models. Thus, dual targeting of CD47 and CTLA-4 selectively depletes T_reg cells and can promote immune responses against solid tumors. Blockade of CD47, the "do not eat me" signal, has limited effects in solid tumors despite its potent antitumor effects in hematopoietic malignancies. Taking advantage of the high expression of cytotoxic T lymphocyte–associated protein 4 (CTLA-4) on T_reg cells and abundant Fc receptor–expressing active phagocytes inside the tumor microenvironment (TME), we designed and tested a heterodimer combining an anti–CTLA-4 antibody, which targets T_reg cells, with the CD47 ligand, signal regulatory protein α (SIRPα), to selectively block CD47 on intratumoral T_reg cells. We hypothesized that heterodimer treatment would increase antibody-dependent cellular phagocytosis of the targeted T_reg cells. We found that anti–CTLA-4×SIRPα preferentially depleted ICOS^high immunosuppressive T_reg cells in the TME and enhanced immunity against solid tumors, including MC38 and CT26 murine colon cancers. Mechanistically, we found that CD47 expression on T_reg cells limited anti–CTLA-4–mediated depletion and Fc on the heterodimer-enhanced depletion. Furthermore, anti-human CTLA-4×SIRPα depleted tumor T_reg cells and exhibits less toxicity than anti-human CTLA-4 in a humanized mouse model. Collectively, these results demonstrate that simultaneously modulating both "eat me" and do not eat me signals induces T_reg cell depletion inside the TME and may be an effective strategy for treating solid tumors. [ABSTRACT FROM AUTHOR]