Theses and Dissertations

Date of Award

7-2022

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry and Molecular Biology

First Advisor

Dr. Bilal Bin Hafeez

Second Advisor

Dr. Manish Tripathi

Third Advisor

Dr. Dae Joon Kim

Abstract

Immune checkpoint blockade (PD1, PDL-1 and CTLA-4) immunotherapies have emerged as the breakthrough in cancer treatment. However, some malignancies show marginal response. One factor that influences the efficacy of immunotherapy is the development of immunosuppressive tumor microenvironment (TME), caused by infiltration of myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAM) into the tumor, facilitating metastatic tumor growth and immunotherapy resistance. We have identified Cucurbitacin B (Cuc. B), a potent small molecule that targets TAM and MDSCs and inhibits Stat3, CSF-1R, and PI3Kγ signaling axis at lower doses compared to the pharmacological inhibitor of PI3Kγ (IPI-549). IL-4 polarization of TAM caused a loss of the phagocytic capacity which we observed to be restored by Cuc. B treatment. Cuc. B treatment also inhibited the expression of PDL-1 in TAMs. Taken together, our results suggest that Cuc. B has the potential to reprogram TAM and MDSCs via targeting Stat3, CSF-1R, and PI3Kγ. Therefore, Cuc B could be a novel therapeutic modality in improving tumor immunity and checkpoint blockade PD-1/CTLA-4 immunotherapy against non-responsive malignancies.

Comments

Copyright 2022 Emmanuel Anning. All Rights Reserved.

https://go.openathens.net/redirector/utrgv.edu?url=https://www.proquest.com/dissertations-theses/cucurbitacin-b-potential-natural-agent-targeting/docview/2742638910/se-2?accountid=7119

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