Kerry S. Campbell, PhD
Office Phone: 215-728-7761
Lab Phone: 215-728-7762
Natural killer (NK) cells constitute about 10-15% of the normal lymphocytes in human peripheral blood. They are important sentinels of the innate immune system that can detect and kill tumor cells and virus-infected cells, and produce cytokines, including interferon-γ and tumor necrosis factor-α. NK cells are regulated by a dynamic balance between positive and negative intracellular signals that are transduced from cell surface activating and inhibitory receptors. This makes them an ideal cellular model system to study signal transduction crosstalk. Our goal is to understand the molecular mechanisms by which NK cells recognize and attack abnormal cells in the body, but are tolerant toward normal cells. This knowledge should lead to therapeutic strategies that can enhance NK cell responsiveness toward tumors and viruses in patients.
Killer cell immunoglobulin-like receptors (KIRs) are key regulators of human NK cell function. KIRs bind major histocompatibility complex class I (MHC-I) molecules on the surfaces of all healthy normal cells in the body. Upon detecting MHC-I, KIRs transduce a negative intracellular signal that suppresses NK cell killing responses. The inhibitory signal derived when KIR detect MHC-I is important for establishing tolerance toward normal cells. Many abnormal tumor cells and virally infected cells eliminate MHC-I expression, however, which abolishes the KIR negative signals and releases the NK cells to specifically attack only these abnormal cells and eliminate them from the body. We are studying the molecular mechanisms controlling the function and surface expression of KIRs. Improved understanding of the regulation of KIR should lead to therapeutic treatments to lower the NK cell activation threshold to more efficiently attack tumor cells and virus-infected cells.
In addition, we are also studying the contributions of NK cells in immune responses toward cancer. Multiparametric flow cytometry is being employed to study the phenotype and function of NK cells in the peripheral blood of cancer patients. Current patient cohorts under study include indolent B cell lymphoma, renal cell carcinoma, melanoma and multiple myeloma. Immunotherapies that enhance NK cell function to treat cancer are also under study, including therapeutic antibodies targeting PD-1, KIR, and SLAMF7. We are characterizing mechanisms by which these antibodies enhance NK cell antitumor responses through blocking inhibitory pathways or initiating antibody dependent cellular cytotoxicity (ADCC) responses.