Harnessing Dendritic Cell Reprogramming to Elucidate Mechanisms of Tumor Immunity

Projekt: Avhandling

Projektinformation

Beskrivning

Recent research unravelled the crucial role of conventional dendritic cells type 1 (cDC1s) in tumor immunity. Clinical studies observed a strong correlation of increased cDC1 numbers in tumors with cancer patient survival and immunotherapy responsiveness. While the positive impact of cDC1 remains to be fully elucidated, the unprecedented ability to cross-present neoantigens and prime protective CD8+ T-cells makes cDC1s central for tumor immunity. However, in tumors cDC1 are rare and the mechanisms governing cross-presentation still incompletely understood. Thus, novel strategies are required to dissect cross-presentation regulation and ensure the functionality within the tumor microenvironment.

Cellular reprogramming is a very promising tool to study the biology of cDC1 and assess their therapeutic potential. In our group, direct lineage conversion has proven successful to reprogram mouse and human fibroblasts into cDC1-like cells using the combined expression of transcription factors PU.1, IRF8 and BATF3. These induced dendritic cells (iDCs) acquire phenotypic, functional, and transcriptional properties of cDC1. Further, employment of the reprogramming factors directly on tumor cells generates functional tumor-antigen presenting cells (tumor-APCs) and imposes a global antigen presentation signature through upregulation of the MHC class I and II pathways. Importantly, overexpression of PU.1, IRF8 and BATF3 endows fibroblasts and tumor cells with the cDC1 hallmark function cross-presentation and naïve CD8+ T-cell priming. This allows to harness the cDC1 reprogramming system to interrogate mechanisms of cross-presentation in the context of tumor immunity.

The aim of this project is to employ fibroblast and tumor cell-derived cDC1-like cells (iDC1s and tumor-APCs) to study regulation of cross-presentation in tumor immunity, circumventing the reliance on rare cDC1s. This reprogramming system opens the opportunity to reveal regulators of cross-presentation, profile the tumor presentome by identification of cross-presented and presented neoantigens and examine the role of cross-presentation in tumor immunity by in vivo reprogramming of tumor cells.
StatusPågående
Gällande start-/slutdatum2022/03/012026/03/01

Samarbetspartner

  • Lunds universitet (huvudsaklig)
  • Asgard Therapeutics AB (Projektpartner)
  • University of Lausanne (Projektpartner)

Ämnesklassifikation (UKÄ)

  • Cell- och molekylärbiologi
  • Immunologi
  • Cellbiologi
  • Immunologi inom det medicinska området