Date of Award

5-2020

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Samuel Z. Soffer, MD

Second Advisor

Marc Symons, PhD

Third Advisor

Bettie M. Steinberg, PhD

Abstract

Osteosarcoma is a highly metastatic primary bone tumor that predominantly affects adolescents and young adults. The presence of metastatic disease severely reduces the overall survival of patients, from nearly 80% to less than 20%. Despite advancements in chemotherapeutic and surgical approaches in the treatment of osteosarcoma, the overall survival for patients with metastatic osteosarcoma has not improved in three decades. As is true for most solid tumors, a mainstay of treatment in osteosarcoma is removal of the primary tumor. However, surgical excision itself has been implicated in promoting tumor growth and metastasis, an effect known as surgery-accelerated metastasis. The underlying mechanisms contributing to surgeryaccelerated metastasis remain poorly understood. However, evidence suggests that the mechanisms driving surgery-accelerated are multifactorial, with several different mechanisms likely contributing to this effect. Among these proposed mechanisms, pro-tumorigenic alterations in immune function have been suggested to be contributory. It has also been demonstrated that tumor-associated macrophages, macrophages present within the microenvironment of solid tumors, play a critical role in the pathogenesis of osteosarcoma through regulation of the tumor microenvironment. While a multitude of macrophage subtypes may exist within the tumor microenvironment, macrophages exhibiting tumor supportive functions predominate in most cancers. These tumor-associated macrophages secrete pro-angiogenic factors, inhibit NK and T-cell function, and facilitate tumor cell extravasation and invasion by promoting stromal remodeling. While many studies have demonstrated the role of tumor-associated macrophages in tumor progression in the primary tumor, less is known about the macrophages present at the metastatic site, metastasis-associated macrophages, which promote later stages of metastasis. Metastasis-associated macrophages appear to promote metastatic tumor development in a manner similar to tumor-associated macrophages by initiating angiogenesis, inhibiting antitumor immune responses, and promoting matrix remodeling making metastasis-associated macrophages potential targets for novel therapeutic intervention to inhibit metastatic development.

In this thesis, I hypothesized that metastasis is enhanced following surgical excision secondary to a pro-tumor macrophage-mediated immunosuppressive metastatic niche. Therefore, modulation of macrophage phenotype to a more anti-tumor state could prevent post-surgical metastatic enhancement. After characterizing a syngeneic murine model surgery-accelerated metastasis in osteosarcoma, I utilized this model to investigate the role that macrophages in the metastatic niche play in baseline metastatic development in osteosarcoma and in surgeryaccelerated metastasis specifically. I then examined whether gefitinib, an already FDA approved medication which I have shown to alters macrophage function to an anti-tumor state through an off-target inhibition of receptor interacting protein kinase 2 (RIPK2), can prevent the metastatic enhancement induced by surgery.

I demonstrate that surgical excision of the primary tumor resulted in increases in lung metastatic surface nodules, overall metastatic burden and number of micrometastatic foci. This post-surgical metastatic enhancement was associated with a shift in macrophage phenotype within the lung to a more pro-tumor state. This was also associated with the production of an overall immunosuppressive pulmonary metastatic niche, as demonstrated by increased predominance of myeloid-derived suppressor cells and reduced numbers of T-cells within the lungs. Treatment with gefitinib prevented tumor-supportive alterations in macrophage phenotype and resulted in reduced metastasis. These data indicate that targeted pharmacologic therapies that prevent pro-tumor changes in macrophage phenotype could be utilized perioperatively to mitigate surgery-accelerated metastasis and improve the therapeutic benefits of surgery.

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