Project #1
Driving Tumor Antigen Presentation by RNA-mediated Transdifferentiation
Cancer is a worldwide health challenge leading to increased mortality and diminishing quality of life of millions of people. In recent years, immunotherapy has transformed cancer treatment, but targeting effectively refractory solid tumours remains a challenge due to poor T cell activation. Downregulation of antigen presentation pathways and lack of professional antigen presenting cells in the tumour microenvironment contribute to immune evasion.
My group (the Pereira Lab) has demonstrated direct reprogramming of fibroblasts or tumour cells into type 1 conventional dendritic cells (cDC1) cells by overexpression of the transcription factors PU.1, IRF8, and BATF3, moving towards clinical application via a viral gene therapy. Despite its promise, this approach has limitations including safety concerns, inefficient targeting of solid tumors in vivo, and scalability.
Thus, we propose to develop in vivo reprogramming of tumour cells into cDC1-like cells using RNA vectors. We will firstly evaluate the capacity of modified linear, self-replicating, and circular RNA encoding the reprogramming factors to reprogram fibroblasts in vitro and assess their antigen presentation and cytokine secretion function. Secondly, RNA-mediated reprogramming of cancer cells will be evaluated, and anti-tumour immunity in vivo assessed as monotherapy or in combination with immune checkpoint blockade. The goal is to optimize RNA vector designs for the most effective in vivo reprogramming considering differences in delivery, expression kinetics and immunogenicity.
Driving Tumour Antigen Presentation by RNA-mediated Transdifferentiation will enable the induction of antigen-presenting phenotypes in cancer cells, leading to potent and specific immunity towards tumour-specific antigens. It will result in an off-the-shelf, safe, and scalable immunotherapy solution that also has the potential to enhance current immunotherapy approaches.
Main principal investigator
Co-supervisors
Immunotherapy by cellular reprogramming. The cover depicts a novel cancer immunotherapy modality by reprogramming tumor cells within the tumor microenvironment into dendritic cells as shown by the Pereira group. eThe key, an adenoviral vector that delivers the reprogramming factors PU.1, IRF8 and BATF3 to tumor cells in vivo unlocked an immunogenic program in tumor cells that started to present antigens as dendritic cells type 1. The dendritic cell-like cells, glowing as a light bulb in the dark cold tumor, illuminate the way for the immune system to target tumors and generate robust, long-lasting, and systemic antitumor immunity. The group now aims to explore RNA delivery to elicit in vivo reprogramming. CREDIT: Joana Carvalho.
Filipe Pereira
Principal Investigator
Phone: +46 46 222 49 19
Email: filipe [dot] pereira [at] med [dot] lu [dot] se
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