Tumor immunity, T lymphocyte effectors, immunotherapy, T-cell dysfunction in cancer, myeloid derived suppressor cells (MDSC) and angiogenesis
Assessing the immunosuppressive and proangiogenic activity of MDSC in human tumors
Determine how typosine kinease Inhibitors (TKI) impair MDSC function and survival
Define the role of MDSC in resistant to TKI therapy
My research effort is directed toward defining the mechanisms by which the tumor microenvironment can negatively influence the development of T cell immunity to cancer. The major focus has been on T cell suppression mechanisms in patients with renal cell carcinoma (RCC). One main project has been to identify those gangliosides that are shed from human RCC and assess their impact on T cell function, including their capacity to modulate cytokine/chemokine gene expression and stimulate T cell apoptosis. Over the past 5 years the role of myeloid derived suppressor cells (MDSCs) in immune dysfunction has become the major focus in my laboratory. We showed that MDSCs were increased in the peripheral blood of RCC patients, and that in vitro depletion of these cells significantly reversed T cell suppression. We also showed that the tyrosine kinase inhibitor (TKI) sunitinib, which is now front line therapy for metastatic RCC, reduces the number of MDSCs in RCC patients and in 4 mouse tumor models, resulting in improved T cell function. We are beginning to define the mechanisms by which sunitinib inhibits MDSC accumulation in tumor bearing hosts, and to test whether the ability of sunitinib to restore T cell responses will improve immunotherapeutic outcomes when combined with vaccines or adoptive T cell therapy. Our current work also suggests that in some tumor models, and perhaps some patients, products locally produced by the tumor (ie, GM-CSF) can render sunitinib-sensitive MDSC resistant to this TKI. Given that MDSC produce both immunosuppressive and proangiogenic molecules, their persistence in select sunitinib treated tumor bearing hosts may represent a mechanism of resistance to sunitinib, thus promoting immune suppression, angiogenesis and tumor progression.
Additional experiments are examining the chemokine/chemokine receptor axis important to the trafficking of MDSC to tumors. Based on preliminary data we propose that tumor and bone marrow MDSC populations consist of distinct cellular subsets characterized by unique patterns of chemokine receptor expression that displays gene expression profiles linked to immunosuppressive and/or pro-angiogenic function. These studies may provide new insight into how to identify and then target MDSC subsets with the most potent tumor promoting activities.
Joanna Ireland, M.S.
Patricia Rayman, M.S.
Charles Tannenbaum, Ph.D.
Brian Rini, M.D., Department of Solid Tumor Oncology, Taussig Cancer Center, Cleveland Clinic
Peter Cohen, Mayo Clinic, Arizona
Walter Storkus, Ph.D., Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
Jennifer Ko, M.D., Ph.D., Pathology Institute, Cleveland Clinic (Resident)
Michael Vogelbaum, M.D., Department of Neurosurgery, Brain Tumor Institute, Cleveland Clinic
Basisakhi Raychaudhuri, Ph.D., Department of Neurosurgery, Brain Tumor Institute, Cleveland Clinic
Ernst Borden, M.D., Department of Solid Tumor, Cleveland Clinic
Dan Lindner, M.D., Ph.D., Taussig Cancer Center, Cleveland Clinic
Raychaudhuri B, Rayman P, Ireland J, Ko J, Rini BI, Borden E, Garcia J, Vogelbaum MA, and Finke J. 2011 Myeloid derived suppressor cell accumulation and function in newly diagnosed glioblastoma patients. Neuro-Oncology, In Press