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CROSSTALK BETWEEN tGLI1 AND PD-L1 IN BREAST CANCER AND ITS IMPACT ON ANTI-TUMOR IMMUNITY

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title
CROSSTALK BETWEEN tGLI1 AND PD-L1 IN BREAST CANCER AND ITS IMPACT ON ANTI-TUMOR IMMUNITY
author
Anguelov, Marlyn
abstract
Breast cancer is the most common cancer diagnosed in women worldwide. Our laboratory discovered an alternative splice variant of glioma-associated oncogene homolog 1 (GLI1), termed truncated GLI1 (tGLI1). tGLI1 is tumor specific and behaves as a gain-of-function GLI1 transcription factor that can regulate many genes and phenotypes in addition to those regulated by GLI1 to intensify the aggressive nature of breast cancer. Our laboratory found that tumors with highly activated tGLI1 are associated with increased metastasis, poor survival and higher incidence of breast cancer metastasis to the brain. However, the molecular mechanisms by which aggressive breast cancer evades the immune system is still not well understood, and tGLI1’s role in anti-tumor immunity has not been investigated. To address this matter, we investigated the role of tumoral tGLI1 in anti-tumor immunity. Herein, we have uncovered novel mechanisms by which tGLI1-expressing breast cancer cells can regulate anti-tumor immunity in the brain microenvironment and systemically. We observed that tGLI1-expressing triple negative breast cancer (TNBC) cells secrete factors that promote microglia to transition into a tumor-supportive (M2) phenotype, although the factors that mediate this transition are still under investigation. Furthermore, we demonstrate that tGLI1 and program death-ligand 1 (PD-L1) are co-expressed in breast cancer and are enriched in TNBC and HER2-enriched breast cancers, the two subtypes that have the highest propensity to metastasize and are associated with significantly poorer overall survival. Tumoral tGLI1 also transcriptionally upregulates PD-L1 expression both in vitro and in vivo to a higher degree than GLI1 in breast cancer. In addition, we demonstrate that tGLI1 and STAT3 co-expression increases PD-L1 promoter activity in vitro and expression in vivo. Lastly, the co-expression of tumoral GLI1 and tGLI1 renders TNBC cells resistant to natural killer cell-mediated killing. These findings uncover a novel role that tumoral tGLI1 plays in immunomodulation, providing a new insight into the biology of tGLI1-positive breast cancer and a rationale to suppress the tGLI1 pathway to overcome resistance to immune checkpoint inhibitors.
subject
anti-tumor immunity
biology
breast cancer
immunotherapy
PD-L1
tGLI1
contributor
Lo, Hui-Wen (committee chair)
Kerr, Bethany (committee member)
date
2020-05-29T08:36:00Z (accessioned)
2021-05-28T08:30:12Z (available)
2020 (issued)
degree
Biomedical Science – MS (discipline)
embargo
2021-05-28 (terms)
identifier
http://hdl.handle.net/10339/96824 (uri)
language
en (iso)
publisher
Wake Forest University
type
Thesis

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