Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Human and Molecular Genetics
First Advisor
Joseph W. Landry
Abstract
There is a significant sex-bias in lung cancer with males showing increased mortality compared to females. If understood mechanistically, these differences could be targeted therapeutically to personalize cancer therapies to each sex. After observing a clear sex-bias in humanized mice, with male patient-derived xenograft (PDX) lung tumors being more progressive and deadlier than female PDX lung tumors, we identified the Lewis Lung Carcinoma (LLC) and CMT-167 mouse tumor models of lung cancer with the same sex-bias. This sex-bias was not observed in models of breast (4T1, E0771), colon (CT26), melanoma (B16-F10), and renal (Renca) cancers. In vivo, the sex-bias in growth and lethality requires intact ovaries, functional innate natural killer (NK) cells and monocytes/macrophages, and the activating receptor Natural Killer Group 2 D (NKG2D). Using ex vivo cell culture models we show that LLC and CMT-167 are sensitized to the anti-cancer effects of NKG2D-mediated NK cell and macrophage killing through the TNF-related Apoptosis Inducing Ligand-B-cell lymphoma extra-large (TRAIL-Bcl-XL) axis when cultured with serum from female mice with intact ovaries. Using both flank and orthotopic models we observe that the Bcl2/Bcl-XL inhibitor navitoclax (ABT-263) improves tumor growth control in female mice and requires NK cells, macrophages, and the TRAIL signaling pathway. This research suggests that navitoclax and a TRAIL pathway agonist could be used as a personalized therapy to improve outcomes in women with lung cancer. Further studies into the role that sex hormones play in modulating lung cancer growth in males and females show a potential role for activin. In vitro studies using sex hormones show that treatment of cells pre-incubated with male mouse serum and activin gain partial sensitivity to NK cell induced apoptosis and TRAIL induced apoptosis. Concurrent studies on the effects of hormone replacement therapy in vivo show that tumors grown in female mice receiving exogenous testosterone grow faster than their untreated counterparts. Studies in additional models of lung cancer, including a chemically induced model and a genetically engineered mouse model (GEMM), show differences in survival and tumor growth between the sexes. Furthermore, studies with anti-PD-L1 therapy show an increased response in males compared to females, providing a basis for further investigations into differences in therapeutic response between the sexes.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-9-2024