800 Dual targeting of CTLA-4 and CD47 on Treg cells rejuvenates immunity against solid tumors

Background Although approved by FDA, anti-CTLA-4 treatment has severe side effect that limits its clinical usage. Blockade of CD47, the “don9t eat me” signal, has limited effects in solid tumors despite its potent anti-tumor effects in hematopoietic malignancies. Targeted delivery of immune blockers into tumor tissues are desireble. Methods Taking advantage of the high expression of CTLA-4 on Treg cells and abundant Fc receptor+ active phagocytes inside the tumor microenvironment (TME), we design and test an anti-CTLA-4×SIRPα (CD47 ligand)-Fc heterodimer that selectively blocks CD47 on intratumoral Treg cells and increases antibody-dependent cellular phagocytosis (the “eat me” signal). Results Anti-CTLA-4×SIRPα preferentially depletes ICOShigh immunosuppressive Treg cells in the TME (figure 1–3) and enhances immunity against solid tumors. Mechanistically, we discovered that CD47 expression on Treg cells limits anti-CTLA-4 mediated depletion while Fc on the heterodimer enhances the depletion. Furthermore, anti-human CTLA-4×SIRPα depletes tumor Treg cells (figure 4–6) and exhibits less toxicity than anti-human CTLA-4 in a humanized mouse model. Conclusions Collectively, these results highlight coordinatively modulating “eat me” and “don9t eat me” signals for depleting Treg cells inside the TME as a unique strategy for solid tumor treatment.