Reprogramming cancer cells into macrophage-like antigen-presenting cells for cancer vaccination

• Applicant: Dr. Sebastian Koschade
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544781037

Tumor vaccination strategies aim to induce a specific response of the patient’s own immune system against tumor antigens. Acute lymphatic leukemia (ALL) cells can be directly reprogrammed into macrophage-like antigen-presenting cells (APC) via lentiviral expression of myeloid transcription factors C/EBPα and PU.1. These reprogrammed ALL cells have phagocytic activity, present tumor antigens, express costimulatory signals and can evoke a potent antileukemic immune response. This does not rely on prior reprogramming into induced pluripotent stem cells and is thus inherently safer for in vivo applications. However, the spectrum of cancer types amenable to this direct reprogramming strategy is currently not known. Likewise, the molecular mechanisms and cell-intrinsic determinants of successful myeloid reprogramming into immunogenic macrophage-like APC are unknown. We therefore aim to determine the spectrum of reprogrammable cancer entities and to identify key determinants of this process using genetic barcoding for clonal tracing and global gene expression profiling techniques on RNA and protein level. In parallel, we aim to establish a therapeutically applicable in vivo reprogramming strategy for ALL, acute myeloid leukemia (AML), diffuse large B cell lymphoma (DLBCL) and pulmonary adenocarcinoma. Instead of the current expression system using lentiviral vectors, we will develop local and systemic delivery of C/EBPα and PU.1 using in vitro transcribed, base-modified mRNA and test its preclinical efficacy. In a further part of the project, we aim to investigate modifications of C/EBPα or PU.1 and additional genetic elements to improve reprogramming efficiency, and specific macrophage-directed co-treatments to improve the effectivity of immune responses. Overall, this project will uncover key determinants of cancer cell myeloid reprogramming into immunogenic antigen-presenting cells and establish C/EBPα und PU.1 mRNA-mediated in vivo reprogramming as a new therapeutic cancer vaccination strategy

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Ravindra Majeti