Year: 2016
Type: dissertation
Abstract: Dendritic cells (DCs) dysfunction in cancer is a well-established phenomenon that is considered one of the key mechanisms of immune evasion. Defects in tumor DCs are caused primarily by tumor-derived factors present in the tumor milieu. However, the mechanisms and the proximal signals that drive this process remain elusive. This thesis explores the molecular mechanisms that drive tumor DC dysfunction. In the first sections of this thesis, I showed the critical importance of tumor-derived toll-like receptor (TLR)-2 ligands in the generation of immunosuppressive Gr-1+ IL-10-producing human and mouse DCs. TLR2 activation induced two parallel synergistic process that converged to activate STAT3: stimulation of autocrine IL-6 and IL-10, and upregulation of their respective cell surface receptors. These processes imprint the capacity of tumor DC in the milieu to respond to lower concentrations of tumor associated cytokines, therefore lowering the STAT3 activation threshold. I identified versican as a soluble tumor-derived factor that ligates with TLR2 to induce DC dysfunction. In the last section of the thesis, I explored the possibility of TLR2 blockade to enhance the efficacy of tumor immunotherapy. TLR2 blockade improved intra-tumor DC immunogenicity. These functional properties was associated with better anti-tumor immune responses elicited by a GM-CSF producing whole cell tumor vaccine (GVAX), and higher rates of proliferation and expansion of adoptively transferred cytotoxic T cells (CTLs). Overall, the findings presented in this thesis provide a basis of understanding the molecular mechanisms of DC dysfunction in cancer and highlight TLR2 as a relevant therapeutic target to improve cancer immunotherapy.
Source: TSpace (University of Toronto)
Author: Michael Tang
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2773056792