Abstract:
Dendritic Cells, particularly conventional dendritic cells (cDC’s), play a critical role in the Tumor Microenvironment (TME), by cross presenting Tumour Associated Antigens (TAA’s) to cytotoxic T cells, for subsequent tumour burden clearance. In this project, we show that DC’s are recruited in higher numbers into the TME of ovarian cancer murine models, thus establishing evidence for the importance of DC in the context of cancer. Through ex-vivo assays, this project demonstrates the TME mediated downregulation of MHC-I molecule and costimulatory molecules which are involved in antigen presentation. While this contrasts with the project’s in-vivo data where MHC-I levels have high variability, it opens a discussion on short-term exposure versus chronic exposure effects of a TME and also highlights the systemic variability of cancer TME in different individual mice. Elevation of DC exhaustion markers, namely PD-L1 and TIM-3 are also reported, hinting at potential targets for immunotherapy in TME. Further, C3-ADP ribosyl transferase, a Clostridium botulinum derived enzyme, is proposed as a neoadjuvant candidate to boost DC-mediated antigen presentation. We show preliminary results where C3 transferase boosts antigen presentation signals in normal conditions and also rescues downregulated levels in TME conditions.
