Advisory Committee Chair
Melissa L Harris
Advisory Committee Members
Steven N Austad
Thomas M Ryan
Daniel L Smith JR
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) College of Arts and Sciences
Immune checkpoint inhibitors have drastically improved cancer treatments and increased the overall survival rate of many cancer patients. Currently, one of the most active areas of research involves inhibitors to the interaction of programmed death 1 (PD- 1) found on T cells and its ligand programmed death-ligand 1(PD-L1) found on tumor cells. However, PD-L1 expression is not limited to cancer cells and physiological expression of PD-L1 can be found in tissues throughout the body. One notable side-effect of anti-PD-1/PD-L1 therapies is the return of pigmentation to previously gray hairs suggesting that quiescent melanocyte stem cells (qMcSCs) are retained gray hairs and that PD-1/PD-L1 signaling has a role in hair follicle pigmentation. The central hypothesis of this dissertation is that qMcSCs of the hair follicle express PD-L1, that qMcSCs vary in depth of quiescence, and that PD-1/PD-L1 signaling plays a role in follicular pigmentation. Using a combination of in vitro and in vivo assays, RNA-sequencing, and bioinformatic analysis, we investigated these questions and found that on average 12% of qMcSCs have increased membrane expression of PD-L1 and are retained with age. Using single-cell RNA sequencing we expand upon these initial observations and find that in fact two populations of Kit+/Cd45- qMcSCs express Pd-l1 and differ based on the expression of early and late melanocytic lineage developmental markers, and quiescence depth. Lastly, we show that blocking PD-1/PD-L1 significantly reduced the intensity of iv hair graying following an acute hair graying event in female mice and in vitro that PD-L1 has a dual role based on proliferation or quiescence in melanocytic cells. Altogether, the work presented in this dissertation provides insight into the molecular heterogeneity of the qMcSC population, shows that two novel subpopulations of qMcSCs express Pd-l1, reveals that quiescence depth varies across qMcSCs, and demonstrates the role of PD-L1 in melanocytic cells, and hair follicle pigmentation. This work sets a solid foundation for future studies investigating the mechanism controlling PD-L1 expression during quiescence in melanocytic cells, determining the human relevancy of our findings, and evaluating changes in immune cell and McSC populations following anti-PD-L1 in the retention of hair pigmentation.
Palmer, Joseph W., "Investigating the Role of a Novel Subpopulation of PD-L1+ Quiescent Melanocyte Stem Cells in Pigmentation" (2023). All ETDs from UAB. 12.
Available for download on Thursday, May 09, 2024