Author ORCID Identifier

https://orcid.org/0000-0002-6494-7872

Date of Graduation

5-2023

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

John Heymach

Committee Member

Don Gibbons

Committee Member

Tina Cascone

Committee Member

Michael Curran

Committee Member

Menashe Bar-Eli

Committee Member

Linghua Wang

Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Targeted therapeutic agents, such as epidermal-like growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) or monoclonal antibodies targeting vascular endothelial growth factor (VEGF/R), can effectively inhibit upregulated signaling pathways driving tumorigenesis in NSCLC and many other cancers. Unfortunately, however, resistance to such targeted therapies inevitably arise in most patients and can occur through a variety of resistance mechanisms including genomic alterations and upregulation of bypass pathways. Additionally, patients who have acquired resistance to these targeted agents typically have tumors characterized by an immunosuppressive tumor microenvironment and thus yield minimal clinical benefit to anti-PD-1/PD-L1 immunotherapy. This work seeks to further elucidate the role of molecular targets, like IL-6 and estrogen, in promoting immunosuppression in NSCLC tumors with acquired resistance to an EGFR-TKI or anti-VEGF therapy. Using preclinical in vitro human NSCLC cell lines and in vivo murine NSCLC models in addition to clinical samples from patients with NSCLC tumors, this study has effectively 1) characterized the role of IL-6 in impairing anti-tumor activity of T cells and NK cells in EGFR-mutant NSCLC tumors which have acquired resistance to EGFR-TKIs and 2) determined the impact of estrogen on increasing myeloid infiltration and secretion of pro-angiogenic factors in NSCLC tumors which are resistance to anti-VEGF therapy. Together, these findings provide a foundation to pursue further studies which determine the clinical utility of therapeutically targeting IL-6 or estrogen signalling in patients with resistant NSCLC disease.

Keywords

EGFR-mutant, NSCLC, immunosuppression, TKI, VEGF, IL-6, NK cells, T cells, EMT, estrogen

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