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Title: In vivo manipulation of Fc gamma receptor expression and activity through macrophage polarization
Author: Dou, Lang
ISNI:       0000 0004 8509 7699
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2017
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Over the last few years, it has become clear that immunotherapy has the potential to eliminate cancer. Macrophages have been shown to play a central role in tumour immunotherapy, especially direct targeting therapy with monoclonal antibodies (mAb). In tumours, macrophage populations are particularly heterogeneous, with several subpopulations of macrophage co-existing in the microenvironment. It has been documented that tumour associated macrophages can contribute to tumour progression and likely impact on the efficacy of immunotherapy. In this project, we have combined various reagents, including toll-like receptor (TLR) agonists and stimulator of interferon genes (STING) ligands with anti-CD20 mAb in an attempt to polarise macrophages towards a pro-inflammatory phenotype to augment mAb efficacy. We found that the TLR3 agonist poly(I:C) polarized macrophages to a proinflammatory phenotype, and significantly promoted B cell depletion in vitro and in vivo by greatly increased the Fc gamma receptors (FcγR) activatory to inhibitory ratio on F4/80+ macrophages. We also demonstrated that B cell depletion using a murine version (Ritm2a) of the anti-human CD20 mAb rituximab is inhibited in the BCL1 lymphoma model. Using the potent IRF3 activator and STING ligand DMXAA we were able to overcome tumour mediated suppression and recover mAb activity. Consistent with these data, DMXAA combined with anti-mouse CD20 mAb 18B12 markedly enhanced survival in the BCL1 lymphoma model leading to cures in ~80-90% of mice. Finally, we demonstrated that mAb against the co-stimulatory molecule 4-1BB (CD137) were able to inhibit tumour growth in an isotype dependent manner via two distinct mechanisms; agonism through activating CD8+ T cells and direct targeting by deleting intratumoural CD4+Foxp3+ regulatory T (Treg) cells. The activity of anti-4-1BB mAb was lost in FcγR deficient mice demonstrating that both mechanisms of action are dependent on FcγR. Further, compared to anti-4-1BB mIgG2a (LOB12.0 mIgG2a) alone, mAb administered in combination with poly(I:C) further suppressed tumour growth leading to earlier regression. Thus, we would surmise that polarizing macrophages to a pro-inflammatory phenotype can be used as a general strategy to promote direct target anti-CD20 mAb and dual mechanism anti-4-1BB mAb activity via manipulation of FcγR expression on F4/80 high tissue resident macrophages. Our results suggest that in addition to modifying mAb to interact better with effector cells, enhancing the function of effector cells such as macrophages may represent a good strategy to improve anti-cancer mAb therapy.
Supervisor: Beers, Stephen ; Glennie, Martin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available