title: Genetically Engineered Macrophages: A Potential Platform for Cancer Immunotherapy.
abstract: In spite of their successes against hematologic malignancies, immunotherapeutic interventions for the treatment of patients with glioblastoma (GBM) have thus far been unsuccessful. This is in part due to the presence of a tumor microenvironment that fosters neoplastic growth and protects the tumor from destruction by the immune system. A novel genetically engineered macrophage-based platform has been developed with the potential to minimize the effects of the suppressive tumor microenvironment and improve innate and adaptive antitumor immune responses. A newly described lentiviral expression system was validated for the generation of transduced monocytes and monocyte-derived macrophages, and transgene expression was shown to be stable over the course of weeks to months, both in vitro and in a mouse xenograft model of GBM. Furthermore, the genetically engineered macrophages (GEMs) neither caused morbidity in animals nor contributed to accelerated tumor growth. The versatility of GEMs is also highlighted by showing that they can be engineered to secrete proteins that either reduce immune suppression, such as the soluble transforming growth factor beta receptor II, or promote immune cell activation, by expressing interleukin 21. There is also the potential to prevent GEM-mediated immune suppression by using the CRISPR system to knock out genes responsible for dysfunction of cytotoxic cells, including interleukin 10 and programmed death-ligand 1. Together, these results suggest that GEMs are an ideal cell type for transforming the tumor microenvironment and enhancing antitumor immunity. Importantly, it is anticipated that these findings will have broad applicability to other types of tumors with microenvironments that currently preclude successful immunotherapeutic approaches.
authors.affiliation: 1 Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute , Seattle, Washington.
authors.forename: Kara W
authors.initials: KW
authors.lastname: Moyes
authors.affiliation: 1 Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute , Seattle, Washington.
authors.forename: Nicole A P
authors.initials: NA
authors.lastname: Lieberman
authors.affiliation: 1 Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute , Seattle, Washington.
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Kreuser
authors.affiliation: 1 Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute , Seattle, Washington.
authors.forename: Harrison
authors.initials: H
authors.lastname: Chinn
authors.affiliation: 2 Department of Pathology, Seattle Children's Hospital, Seattle, Washington.
authors.forename: Conrad
authors.initials: C
authors.lastname: Winter
authors.affiliation: 2 Department of Pathology, Seattle Children's Hospital, Seattle, Washington.
authors.forename: Gail
authors.initials: G
authors.lastname: Deutsch
authors.affiliation: 1 Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute , Seattle, Washington.
authors.forename: Virginia
authors.initials: V
authors.lastname: Hoglund
authors.affiliation: 1 Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute , Seattle, Washington.
authors.forename: Reid
authors.initials: R
authors.lastname: Watson
authors.affiliation: 1 Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute , Seattle, Washington.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Crane
mesh_terms: D000818:Animals; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D059016:Tumor Microenvironment / Q000276:immunology*
keywords: CRISPR; Vpx; glioblastoma; immunotherapy; macrophages; tumor microenvironment