The role of the dendritic cell receptor DNGR-1 in anti-cancer immunity
File(s)
Author(s)
Lim, Kok Haw Jonathan
Type
Thesis
Abstract
Most successful immunotherapeutic strategies harness CD8+ cytotoxic T cells to kill cancer cells. Central to this process are professional antigen presenting cells called type 1 conventional dendritic cells (cDC1s) that prime and restimulate anti-tumour CD8+ cytotoxic T cells. cDC1s express high levels of DNGR-1, also known as CLEC9A, a C-type lectin receptor that binds filamentous-actin (F-actin). The latter is exposed on dead cell debris ingested by cDC1 and the ensuing triggering of DNGR-1 facilitates cross-presentation of dead cell-associated antigens. It is generally thought that death of tumour cells is a pre-requisite for acquisition of tumour antigens by cDC1. However, whether DNGR-1 is required for CD8+ T cell-mediated immunity to cancer remains unknown. In this thesis, I set out to investigate the role of DNGR-1 in anti-cancer immunity.
Firstly, in a series of in vivo loss-of-function experiments with DNGR-1-deficient mice, I show that DNGR-1 is dispensable for the control and/or rejection of a variety of immunogenic transplantable tumours. I also show that DNGR-1 is redundant for tumour control following therapy-induced immunogenic cell death. However, we recently identified a plasma protein called secreted gelsolin (sGSN) that competes with DNGR-1 for binding to F-actin and acts as a negative regulator of DNGR-1-mediated cross-presentation. I therefore also tested mice mice lacking sGSN and found that loss of sGSN results in DNGR-1-mediated tumour control being unleashed and enhanced responses to a repertoire of anti-cancer therapies including chemotherapy, targeted therapy, immune-checkpoint inhibitors and radiotherapy. In a separate set of studies, I moved away from transplantable tumours to assess the importance of DNGR-1 as an immune barrier to chemical carcinogenesis. Using the 3-methylcholanthrene-induced sarcoma model, I found that DNGR-1-deficient mice displayed increased susceptibility to tumour development compared to WT mice...
Firstly, in a series of in vivo loss-of-function experiments with DNGR-1-deficient mice, I show that DNGR-1 is dispensable for the control and/or rejection of a variety of immunogenic transplantable tumours. I also show that DNGR-1 is redundant for tumour control following therapy-induced immunogenic cell death. However, we recently identified a plasma protein called secreted gelsolin (sGSN) that competes with DNGR-1 for binding to F-actin and acts as a negative regulator of DNGR-1-mediated cross-presentation. I therefore also tested mice mice lacking sGSN and found that loss of sGSN results in DNGR-1-mediated tumour control being unleashed and enhanced responses to a repertoire of anti-cancer therapies including chemotherapy, targeted therapy, immune-checkpoint inhibitors and radiotherapy. In a separate set of studies, I moved away from transplantable tumours to assess the importance of DNGR-1 as an immune barrier to chemical carcinogenesis. Using the 3-methylcholanthrene-induced sarcoma model, I found that DNGR-1-deficient mice displayed increased susceptibility to tumour development compared to WT mice...
Version
Open Access
Date Issued
2022-07-20
Date Awarded
01/12/2022
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Reis e Sousa, Caetano
Strid, Jessica
Sponsor
Wellcome Trust (London, England)
Grant Number
PS3284 (sub-award from 203928/Z/16/Z); Wellcome Trust Ref: 216327/Z/19/Z
Publisher Department
Department of Immunology and Inflammation
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)