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 surface expression of KIRs. Improved understanding of the regulation of KIR surface expression should lead to therapeutic treatments to alter their surface expression and thereby change the NK cell activation threshold to more efficiently attack tumor cells and virus-infected cells.
Alternatively, KIR2DL4 is an activating receptor that stimulates NK cells to secrete cytokines, but uniquely does not stimulate tumor cell killing. Interestingly, KIR2DL4 is only expressed on a small subset of NK cells. Furthermore, receptor expression is upregulated in stimulated NK cells, and some individuals cannot express this receptor at all, due to a common genetic polymorphism. The physiological implications and potential for disease susceptibility resulting from the inability to express KIR2DL4 in some individuals are currently unknown and warrant further detailed study. Our overall goals are to define the molecular mechanisms controlling the unique expression and function of KIR2DL4. The results will allow us to better understand its role in regulating inflammation and fighting cancer.
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, and multiple myeloma. Immunotherapies that enhance NK cell function to treat cancer are also under study, including antibodies targeting PD-1, KIR, and SLAMF7.
Fox Chase Programs
- Grier, J.T., Forbes, L.R., Monaco-Shawver, L., Oshinsky, J., Atkinson, T.P., Moody, C., Pandey, R., Campbell, K.S., and Orange, J.S. (2012) Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J. Clin. Invest., 122:3769-3780. PMCID: 3461929.
- Campbell, K.S., and Hasegawa, J. (2013) NK cell biology: an update and future directions. J. Allergy Clin. Immunol., 132:536-544, PMCID: 3775709.
- Brusilovsky, M., Cordoba, M., Rosental, B., Hershkovitz, O., Andrake, M.D., Pecherskaya, A., Einarson, M.B., Zhou, Y., Braiman, A., Campbell, K.S.*, and Porgador, A.* (2013) Genome-wide siRNA screen reveals a new cellular partner of NK cell receptor KIR2DL4: heparan sulfate directly modulates KIR2DL4-mediated responses. J. Immunol., 191:5256-5267. PMCID: 3836631. *Corresponding authors<
- Mentlik James, A., Cohen, A.D., and Campbell, K.S. (2013) Combination therapies to enhance anti-tumor responses by NK cells. Front. Immunol., 4:481, PMCID: 3870292.
- MacFarlane 4th, A.W., Jillab, M., Plimack, E.R., Hudes, G.R., Uzzo, R.G., Litwin, S., Dulaimi, E., Al-Saleem, T., and Campbell, K.S. (2014) PD-1 expression on peripheral blood cells increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor resection. Cancer Immunol. Res., 2:320-331. PMCID: 4007343.
- Purdy, A.K., Alvarez-Arias, D.A., Oshinsky, J., James, A.M., Serebriiskii, I., and Campbell, K.S. (2014) The AP-2 clathrin adaptor mediates endocytosis of an inhibitory killer cell Ig-like receptor (KIR) in human NK cells. J. Immunol., 193:4675-4683. PMCID: PMC4269369.