Item Details

abstract

Cancer immunotherapies have revolutionized the treatment of cancer; however, only a subset of patient’s respond to these therapeutics. Therefore, predictive biomarkers and therapeutic targets are needed to improve patient response. The integral membrane protein, CD47, is an intriguing therapeutic target as it alters innate and adaptive antitumor immune cell function when interacting with the ligands SIRPα and thrombospondin-1 (TSP1). To our knowledge, it is unknown how CD47 expression impacts cancer cells and the tumor microenvironment. Therefore, to determine if CD47 is a suitable target for cancer immunotherapy treatment, I examined the impact of CD47 on cancer cells and cytotoxic (CD8+) T cells. CD47 differentially regulated several metabolic pathways in both normal and malignant tissue. However, the absence of CD47 in cancer cells altered metabolic pathways associated with proliferation, inflammation, immunosuppression and metabolism, making cancer cells more susceptible to antitumor immune cell killing. On the other hand, the ligation of CD47 on CD8+ T cells by TSP1 impaired activation, proliferation, antitumor function and metabolism; however, these functions were restored by targeting CD47 to continue cancer cell cytolysis. Due to the inverse effects CD47 has on CD8+ T cells and cancer cells, we targeted CD47 in a melanoma and triple-negative breast cancer (TNBC) model, which differ in immunogenicity, and observed a decrease in tumor burden due to an increase in antitumor CD8+ T cells. In addition, targeting CD47 sensitized melanoma and TNBC tumors to immune checkpoint blockade therapy to enhance efficacy and further decrease tumor burden. Together, the systemic delivery of CD47 targeted therapeutics as a monotherapy or in combination with FDA approved immune checkpoint blockades would make cancer cells susceptible to CD8+ T cells enhanced cytolytic activity, resulting in decreased tumor burden. In addition, analysis of TNBC and melanoma tumors and liquid biopsies revealed that the CD47/TSP1 signaling axis could serve a predictive biomarker of immune checkpoint blockade response, providing an opportunity to personalize treatment regimens for cancer patients. Throughout my dissertation we uncovered that CD47 has the potential to be a predictive biomarker of therapeutic response in addition to a therapeutic target for treating cancer.

subject

CD47

Immunotherapy

Melanoma

Metabolism

Triple-negative breast cancer

contributor

Stirling, Elizabeth Rose (author)

Soto-Pantoja, David R (committee chair)

Alexander-Miller, Martha A (committee member)

Cook, Katherine L (committee member)

Deep, Gagan (committee member)

Triozzi, Pierre L (committee member)

date

2022-05-24T08:35:53Z (accessioned)

2023-05-23T08:30:14Z (available)

2022 (issued)

degree

Cancer Biology (discipline)

embargo

2023-05-23 (terms)

identifier

http://hdl.handle.net/10339/100726 (uri)

language

en (iso)

publisher

Wake Forest University

title

CD47 IS A NOVEL TARGET FOR CANCER IMMUNOTHERAPY TREATMENT

type

Dissertation