Abstract
Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%.
Highlights
Chimeric antigen receptors (CARs) are synthetic transmembrane receptors that redirect T cell activity towards clinically relevant targets
To program engulfment towards a target antigen, we created a CAR strategy using the CAR-T design as a guide (Fesnak et al, 2016). We call this new class of synthetic receptors Chimeric Antigen Receptors for Phagocytosis (CAR-Ps)
We made a receptor containing an extracellular antigen CD19 (aCD19) antibody fragment and a cytoplasmic GFP, but no signaling domain, to test whether adhesion mediated by the aCD19 antibody fragment is sufficient to induce engulfment (Figure 1a; CAR-PGFP)
Summary
Chimeric antigen receptors (CARs) are synthetic transmembrane receptors that redirect T cell activity towards clinically relevant targets (reviewed in [Lim et al, 2017; Fesnak et al, 2016]). Macrophages are uniquely capable of penetrating solid tumors, while other immune cells, like T cells, are physically excluded or inactivated (Lim et al, 2017; Lee et al, 2016). Cancer Biology Cell Biology eLife digest Our immune system constantly patrols our body, looking to eliminate cancerous cells and harmful microbes It can spot these threats because it recognizes certain signals at the surface of dangerous cells. T cells that carry CARs are already used to treat people with blood cancers These immune cells are not good at penetrating a solid tumor to kill the cells inside, which limits their use. We report a family of chimeric antigen receptors that activate phagocytosis of cancer cells based on recognition of defined cell surface markers, resulting in significantly reduced cancer cell growth
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
