Genetically modified IL2 bone-marrow-derived myeloid cells reprogram the glioma immunosuppressive tumor microenvironment

Alessandro Canella; Matthew Nazzaro; Sakthi Rajendran; Claire Schmitt; Abigail Haffey; Giovanni Nigita; Diana Thomas; Justin M Lyberger; Gregory K Behbehani; Nduka M Amankulor; Elaine R Mardis; Timothy P Cripe; Prajwal Rajappa

doi:10.1016/j.celrep.2023.112891

Genetically modified IL2 bone-marrow-derived myeloid cells reprogram the glioma immunosuppressive tumor microenvironment

Cell Rep. 2023 Aug 29;42(8):112891. doi: 10.1016/j.celrep.2023.112891. Epub 2023 Jul 28.

Affiliations

¹ The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
² Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
³ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
⁴ Department of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁵ Department of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA.
⁶ Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
⁷ The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
⁸ Center for Childhood Cancer, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
⁹ The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address: prajwal.rajappa@nationwidechildrens.org.

PMID: 37516967
DOI: 10.1016/j.celrep.2023.112891

Abstract

Gliomas are one of the leading causes of cancer-related death in the adolescent and young adult (AYA) population. Two-thirds of AYA glioma patients are affected by low-grade gliomas (LGGs), but there are no specific treatments. Malignant progression is supported by the immunosuppressive stromal component of the tumor microenvironment (TME) exacerbated by M2 macrophages and a paucity of cytotoxic T cells. A single intravenous dose of engineered bone-marrow-derived myeloid cells that release interleukin-2 (GEMys-IL2) was used to treat mice with LGGs. Our results demonstrate that GEMys-IL2 crossed the blood-brain barrier, infiltrated the TME, and reprogrammed the immune cell composition and transcriptome. Moreover, GEMys-IL2 extended survival in an LGG immunocompetent mouse model. Here, we report the efficacy of an in vivo approach that demonstrates the potential for a cell-mediated innate immunotherapy designed to enhance the recruitment of activated effector T and natural killer cells within the glioma TME.

Keywords: CP: Cancer; CP: Immunology; GEMys; IL2; LGG; RCAS/t-va; TME; genetically engineered myeloid cells; immunotherapy; interleukin-2; myeloid cells; reprogramming TME.