Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Dennis E. Discher

Abstract

The ability of a macrophage to engulf and break down invading cells and other targets provides a first line of immune defense in nearly all tissues. This defining ability to ‘phagos’ or devour can subsequently activate the entire immune system against foreign and diseased cells, and progress is now being made on a decades-old idea of directing macrophages to phagocytose specific targets such as cancer cells. Physical properties of cancer cells influence phagocytosis and relate via cytoskeleton forces to differentiation pathways in solid tumors. Here, SIRPα on macrophages from mouse and human marrow was inhibited to block recognition of CD47, a ‘marker of self.’ These macrophages were then systemically injected into mice with fluorescent human tumors. Within days, the tumors regressed, and fluorescence analyses showed that the more the SIRPα-inhibited macrophages engulfed, the more they accumulated within tumors. In vitro phagocytosis experiments on transwells revealed that macrophage migration through micropores was inhibited by eating. However, during the 1-2 weeks of tumor residency, donor macrophages quickly differentiated toward non-phagocytic, high-SIRPα tumor associated macrophage. Analyses of macrophages on soft or stiff collagenous gels demonstrated a stiffness-driven upregulation of SIRPα. Tissue stiffness also seems to have a role in the development of cancer. Meta-analyses suggest that genomic variation across tumors scales with the stiffness of the tumor tissue of origin. These genomic changes give rise to neoantigens that are important for the development of monocyte/macrophage immunotherapies. Indeed, marrow-derived macrophages can phagocytose melanoma cells and present neoantigens leading to the activation of T-cells. Unlike past injections of anti-CD47 which cause anemia, no measurable impact on blood profiles, weight, or development of GvHD was observed from systemic injections of SIRPα-inhibited donor macrophages.

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