Spatiotemporal dynamics of the dendritic cell network in cancer
File(s)
Author(s)
Piot, Cécile
Type
Thesis
Abstract
Type 1 conventional dendritic cells (cDC1s) play crucial roles in inducing CD8+ T cell-mediated cytotoxic activity against tumour cells, which is a central axis of immune-mediated tumour rejection. cDC1s cross-present tumour antigens to CD8+ T cells in lymph nodes (LNs) but also perform key functions within tumours to sustain CD8+ T cell activity.
Fundamental to their ability to perform these functions, cDC1s must be replenished by cDC precursors (pre-cDCs) in tumours and be activated in a manner that enable them to coordinate the anti-tumour response. In this work, I explored both aspects by investigating pre-cDCs recruitment and regulation in tumours, and by characterizing how cDC1s are organized and activated in time and in space during an anti-tumour response. I described that the kinetics of pre-cDCs mobilization from the BM and recruitment to tumours occur at a slower rate as compared to other acute immune challenges and that their differentiation in tumours is not regulated by DNGR-1, a receptor that binds to F-actin exposed on tumour cells. I showed that cDC1s occupy two main regions of the tumour during an immunogenic response, and that their spatial organization might be important for the response since their distribution was altered in uncontrolled tumours. Using inducible lineage tracing methods, I found that a large fraction of cDC1s remained resident “long term” in the tumour, suggesting that different spatiotemporal behaviours might be important for the response. Last, I described that activated tumour cDC1s can exist in two states, characterized by Il12b/Ccr7 or Cxcl9 expression respectively, and that localized in different regions of the tumour, suggesting that different flavours of activated cDC1 might perform different functions in tumours. Future work delineating the mechanisms that regulate these distribution patterns, spatiotemporal dynamics and activation programs might uncover axes by which cDC1s can be harnessed to improve cancer treatments.
Fundamental to their ability to perform these functions, cDC1s must be replenished by cDC precursors (pre-cDCs) in tumours and be activated in a manner that enable them to coordinate the anti-tumour response. In this work, I explored both aspects by investigating pre-cDCs recruitment and regulation in tumours, and by characterizing how cDC1s are organized and activated in time and in space during an anti-tumour response. I described that the kinetics of pre-cDCs mobilization from the BM and recruitment to tumours occur at a slower rate as compared to other acute immune challenges and that their differentiation in tumours is not regulated by DNGR-1, a receptor that binds to F-actin exposed on tumour cells. I showed that cDC1s occupy two main regions of the tumour during an immunogenic response, and that their spatial organization might be important for the response since their distribution was altered in uncontrolled tumours. Using inducible lineage tracing methods, I found that a large fraction of cDC1s remained resident “long term” in the tumour, suggesting that different spatiotemporal behaviours might be important for the response. Last, I described that activated tumour cDC1s can exist in two states, characterized by Il12b/Ccr7 or Cxcl9 expression respectively, and that localized in different regions of the tumour, suggesting that different flavours of activated cDC1 might perform different functions in tumours. Future work delineating the mechanisms that regulate these distribution patterns, spatiotemporal dynamics and activation programs might uncover axes by which cDC1s can be harnessed to improve cancer treatments.
Version
Open Access
Date Issued
2023-11-21
Date Awarded
2024-04-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Reis e Sousa, Caetano
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)