Natural Killer (NK) cells are a unique subset of innate lymphoid cells that function to kill tumor cells and regulate the tumor microenvironment (TME). Head and neck squamous cell carcinomas (HNSCCs) remain poorly responsive to immunotherapy both clinically and preclinically. Recent evidence has demonstrated that activation of NKs with antibody-based therapy can activate effector T cells and improve response in patients with recurrent disease. Likewise, Dendritic Cells (DCs) have been identified as key players in NK cell mediated immunomodulation of the TME. Little, however, has been done exploring how NKs regulate the immune TME in HNSCC, or the effect radiation therapy (RT) has on NK cell activation even though RT is a mainstay treatment for this cancer. Our past work has identified the use of anti-CD25 antibody as a method of depleting regulatory T cells and overcoming resistance to RT. However, preliminary data shows that NK cells express CD25, and are a necessary component of anti-CD25 therapy. This project has two objectives; (1) examine how anti-CD25 therapy influences NK cell populations and its role in overcoming resistance to RT (2) understand how NKs and Dendritic cells (DCs) contribute to tumor recognition and killing in HNSCC. Specific Aims: (1) Characterize the phenotypic, cellular, and molecular effects of targeting the IL-2 receptor (CD25) on NK cells in HNSCCs models treated with RT. (2) understand how NKs, DCs, and Teffector cells interact to induce tumor recognition and killing in HNSCC. Study Design: In this study I will explore the immunomodulatory role of NK cells and DCs within the TME. I will use antibodies therapies to activate NK cells within the TME. In addition, I will utilize genetic knockout mice, available through my collaborators, which lack IL-15, FLT3L and dendritic cells. These mice will allow me to perform loss of function as well as gain/rescue of function studies to understand the mechanistic interactions of these cell types within the TME. I will use flow cytometry to assess cell recruitment and activation within the TME in the knockout mice and after specifically targeted therapies and cell depletions. In addition, single cell RNAseq will be used to characterize intrinsic changes to NK cell populations. Finally, I will use automated quantitative pathology imaging analysis by VECTRA to visualize the interactions our target populations within the TME. Health Significance: These studies will help understand the role of NK cells and DCs in HNSCC. NK cells show strong immunomodulatory potential in the TME through recruitment of DCs, but our preliminary studies have identified the presence of inactive NK cells within HNSCC. As this cancer commonly develops resistance to RT, I hope to identify ways to overcome this resistance through the use of immunotherapies that target NK cells. This will also be clinically relevant as FLT3L therapy has recently entered phase IIb clinical trials.

F32DE030695

2021-07-01

2022-06-30