Date of Award

January 2020

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Marcus Bosenberg

Abstract

Fibroblasts are the most abundant cell type in the tumor stroma, yet their precise role in tumor progression and immune-mediated regression remains unclear. In this work, we characterized the spatiotemporal dynamics of cancer-associated fibroblasts in the melanoma microenvironment using the YUMMER murine melanoma models. We found that early in tumor development, fibroblasts are evenly distributed throughout the tumor parenchyma, but as tumors grow and evade immune suppression, fibroblasts are gradually excluded from the center of the tumor and form a concentrated rim at the tumor edge. However, interestingly, in immune checkpoint inhibitor-treated melanomas, fibroblasts re-infiltrate the tumor at the height of the anti-tumor immune response, forming dense bands through the tumor center. Finally, we examined spatial patterns of fibroblast distribution in human melanocytic lesions and found that similarly, fibroblasts are absent from the parenchyma of primary melanomas, aggregating at their deep invasive margin. Together, these findings suggest that fibroblast exclusion from the tumor core is a marker of progressing tumors and targeting this exclusion mechanism may represent a potential therapeutic strategy for melanoma.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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