Date of Award

January 2013

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Robert E. Tigelaar

Second Advisor

Oscar R. Colegio

Subject Area(s)

Medicine, Immunology, Oncology

Abstract

Inflammation has long been associated with tumorigenesis. Macrophages are cells of the innate immune system, whose density within tumors correlates with a worsening clinical prognosis in most types of tumors. Macrophages have been demonstrated to contribute to the initiation, growth, invasion, and metastasis of tumors. We hypothesized that macrophage density and phenotype differs between squamous cell carcinomas and basal cell carcinomas, two skin cancers with relatively aggressive and indolent clinical behaviors, respectively. Through immunohistochemical analysis, we determined that squamous cell carcinomas have a 5-fold higher density of macrophages than basal cell carcinomas. Tumor-associated macrophages exhibit two classic states of activation. M1 macrophages are inflammatory and are involved in clearance of microorganisms and tumor cells. By contrast, M2 macrophages are involved in tissue remodeling, angiogenesis, and are tumor-promoting. Using flow cytometric analysis of fresh clinical specimens, we determined that macrophages from squamous cell carcinomas express significantly higher levels of M1 (CD40, CD127) and M2 (arginase I) markers as well as higher levels of MMP-9, a pivotal enzyme in tumor matrix remodeling and tumor invasion, than macrophages from the basal cell carcinomas. To determine whether the Toll-like receptor (TLR) agonist imiquimod, an FDA-approved treatment for superficial basal cell carcinoma and actinic keratoses, alters the activation state of tumor-associated macrophages, we studied in vitro and in vivo effects of imiquimod on macrophages. We determined that imiquimod activates primary macrophages from human squamous cell carcinoma to an M1, pro-inflammatory immunophenotype. This phenotype was associated with enhanced macrophage-induced apoptosis of cultured epidermoid carcinoma cells and enhanced phagocytosis of fluorescently labeled tumor cells. Our findings suggest that tumor-associated macrophages play a critical role in pathophysiology of two common human skin cancers. Further, we provide a novel mechanism of action of imiquimod, which provides potential insights in the utilization of immunomodulatory therapies in the treatments of a wider variety of cancers.

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