Chen et al. demonstrated that an enhanced synthetic phagocytosis receptor (eSPR), which integrated FcRγ-driven phagocytic chimeric antigen receptors (CARs) with built-in secreted CD47 blockers, activated both the innate and adaptive immune systems to mount effective antitumor immune response and overcome tumor antigen heterogeneity. The eSPR macrophages showed a proinflammatory phenotype, rejected tumor repolarization, instilled pro-inflammatory traits into the TIME, and cross-presented antigens to T cells to elicit durable tumor control. The eSPR system functionality was further validated in ex vivo-differentiated primary human macrophages.
Contributed by Shishir Pant
ABSTRACT: Macrophage-based cancer cellular therapy has gained substantial interest. However, the capability of engineered macrophages to target cancer heterogeneity and modulate adaptive immunity remains unclear. Here, exploiting the myeloid antibody-dependent cellular phagocytosis biology and phagocytosis checkpoint blockade, we report the enhanced synthetic phagocytosis receptor (eSPR) that integrate FcR_-driven phagocytic chimeric antigen receptors (CAR) with built-in secreted CD47 blockers. The eSPR engineering empowers macrophages to combat tumor antigen heterogeneity. Transduced by adenoviral vectors, eSPR macrophages are intrinsically pro-inflammatory imprinted and resist tumoral polarization. Transcriptomically and phenotypically, eSPR macrophages elicit a more favorable tumor immune landscape. Mechanistically, eSPR macrophages in situ stimulate CD8 T cells via phagocytosis-dependent antigen cross-presentation. We also validate the functionality of the eSPR system in human primary macrophages.
Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (2) City of Hope National Medical Center, Duarte, CA, USA. (3) Department of Immuno-On
Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (2) City of Hope National Medical Center, Duarte, CA, USA. (3) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (4) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (5) Cardiovascular Research Institute & Department of Physiology, University of California, San Francisco, San Francisco, CA, USA. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. (6) Integrative Genomics Core, Beckman Research Institute, City of Hope, Duarte, CA, USA. (7) Cardiovascular Research Institute & Department of Physiology, University of California, San Francisco, San Francisco, CA, USA. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. (8) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (9) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. City of Hope National Medical Center, Duarte, CA, USA. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, CA, USA. (10) Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medicine, Stanford, CA, USA. Department of Pathology, Stanford Medicine, Stanford, CA, USA. (11) City of Hope National Medical Center, Duarte, CA, USA. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. Beckman Research Institute, City of Hope, Duarte, CA, USA. (12) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. mfeng@coh.org.
