Date of Graduation

2018

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

David J Klinke

Committee Co-Chair

Robert K Griffith

Committee Member

Jason D Huber

Committee Member

Yuxin Liu

Committee Member

Yon Rojanasakul

Abstract

Melanoma and breast cancers account for a large number of cancer diagnoses and deaths, with 1 in 28 and 1 in 8 developing melanoma or breast cancer, respectively, in their lifetime. T Lymphocytes play a pivotal role in the immune system response to cancers and are known to evade the immune system by a variety of mechanisms, including modulation of cytokine function. A cytokine important for the function of T lymphocytes, Interleukin-12, and modulation of its Janus Kinase and activators of transcription (JAK-STAT) signaling pathway, plays a role in the immune response to tumors, especially melanoma. We examined the role of interleukin-12 receptor beta 2 as a possible target of immune system inhibition by melanoma via a cytokine sink and initiation of alternative signaling pathways to produce cell survival in melanoma, even when challenged with the cytotoxic stressor and chemotherapy drug imatinib. Additionally, exosomes, nano-sized vesicles containing immune system-inhibiting proteins and nucleic acids, have also been described as a potential mechanism of evasion. We investigated the proteomic profiles of exosomes in human breast cancers, which informed upon studies examining the nucleic acid payloads in murine melanomas against a murine cytotoxic T lymphocyte model, CTLL2 cells. We have examined the microRNA contents of exosomes from a murine B16F0 melanoma line and determined possible target cell alterations in mitochondrial respiration, DNA modification, and targeting of the Notch pathway. We concluded tumor-derived exosomes may affect the overall function of immune cells like cytotoxic T lymphocytes, and specific microRNAs and protein products contained within them may alter cell energetics and certain transcription and translation products to promote the proliferation and immune evasion abilities of melanoma, breast, and other cancers.

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