Glioblastomas are a highly malignant type of brain tumor with very few treatment options. Efforts in Dr. Harrison’s laboratory are directed toward understanding mechanisms by which immune cells contribute to tumor progression and resistance to immunotherapies. The development and application of chemokine receptor antagonists to treat human high-grade glioma patients is a primary goal of the laboratory.
My laboratory has a long history of characterizing roles of chemokines in various physiological and pathological states of the central nervous and cardiovascular systems. Of particular emphasis has been the study of the chemokine fractalkine (CX3CL1) and its receptor, CX3CR1, as well as more recent efforts to target the CCL2/CCL7/CCR2 axis.
Historically, the scope of the research program has included in vitro and in vivo approaches that include 1) structure-function analysis of chemokines and chemokine receptors, 2) studies on the regulation of expression of chemokines and chemokine receptors, 3) understanding signaling mechanisms associated with chemokine receptor activation, 4) use of chemokine receptor-deficient mice, to address the role of various chemokine systems in disease, with recent focus on using these mice to understand the roles of chemokine in malignant glioma, and 5) use of chemokine receptor antagonists in animal models of glioblastoma.
Takacs, G., J. Flores-Toro, and J.K. Harrison. Modulation of the chemokine/chemokine receptor axis as a novel approach for glioma therapy. Pharmacology & Therapeutics 222:107790, 2021.
Rahman, M., G. Sawyer, S. Lindhorst, L.P. Deleyrolle, J.K. Harrison, A. Karachi, F. Dastmalchi, J.A. Flores-Toro, D.A. Mitchell, M. Lim, M.R. Gilbert, and D.A. Reardon. Adult immuno-oncology: using past failures to inform the future. Neuro-oncology 22:1249-1261, 2020.
Flores-Toro, J., D. Luo, A, Gopinath, M.R. Sarkisian, J.J. Campbell, I.F. Charo, R. Singh, T.J. Schall, M. Datta, R.K. Jain, D.A. Mitchell, and J.K. Harrison. CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas. Proc. Natl. Acad. Sci. 117:1129-1138, 2020.
Pham, K., D. Luo, D.W. Siemann, B.K. Law, B.A. Reynolds, P. Hothi, G. Foltz, and J.K. Harrison. VEGFR inhibitors upregulate CXCR4 in VEGF receptor-expressing glioblastoma in a TGFβR signaling-dependent manner. Cancer Letters. 360:60-67, 2015.
Pham, K., D. Luo, C. Liu, and J.K. Harrison. CCL5, CCR1, and CCR5 in murine glioblastoma: immune cell infiltration and survival rates are not dependent on individual expression of either CCR1 or CCR5. J. Neuroimmunol. 246:10-17, 2012.
Liu, C., D. Luo, B.A. Reynolds, G. Meher, A. Katritzky, B. Lu, C. Gerard, C. Bhadha, and J.K. Harrison. Chemokine receptor CXCR3 promotes growth of glioma. Carcinogenesis 32:129-137, 2011.
Liu, C, D. Luo, W.J. Streit, and J.K. Harrison. CX3CL1 and CX3CR1 in the GL261 murine model of glioma: CX3CR1 deficiency does not impact tumor growth or infiltration of microglia and lymphocytes. J. Neuroimmunol. 198:98-105, 2008.