Chimeric antigen receptors that trigger phagocytosis

Elife. 2018 Jun 4:7:e36688. doi: 10.7554/eLife.36688.

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%.

Keywords: Chimeric Antigen Receptor; Fc Receptor; cancer biology; cell biology; human; macrophages; mouse; phagocytosis; receptors; signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / metabolism
  • Antigens, Neoplasm / metabolism
  • Cell Line, Tumor
  • Humans
  • Immunological Synapses
  • Macrophages / metabolism
  • Mice
  • Microspheres
  • NIH 3T3 Cells
  • Phagocytosis*
  • Phosphorylation
  • Receptors, Chimeric Antigen / metabolism*
  • Signal Transduction
  • Silicon Dioxide

Substances

  • Antigens, CD19
  • Antigens, Neoplasm
  • Receptors, Chimeric Antigen
  • Silicon Dioxide