Our lab studies strategies to augment anti-tumor immunity targeting multiple myeloma. Specifically, there are two major projects. The first involves examining the role of marrow infiltrating lymphocytes (MILs) within the tumor microenvironment. The clinical studies have primarily focused on utilizing these highly active tumor specific lymphocytes in adoptive immunotherapy protocols. Laboratory strategies are currently examining ways to augment the efficacy of adoptive T cell therapy with MILs and to examine factors present within the bone marrow microenvironment that regulate their function including their role in the pathogenesis of osteolytic bone damage in myeloma.
Another focus of our lab has been to study the role of myeloid derived suppressor cells (MDSCs) as mediators of tumor-induced immune suppression. These cells exert their immune suppressive function through the production of nitric oxide and arginase-1. We have recently described the ability of phosphodiesterase-5 inhibitors to abrogate the immunosuppressive function of MDSCs. To date, MDSCs have mostly been described in solid tumors. We are examining their role in tolerance induction in myeloma and other malignancies of the bone marrow.
- Borrello, I. (2009). Lenalidomide in renal insufficiency – balancing the risks and benefits. Br J Haematol 144, 446-447. PMID: 19120361
- Luznik, L., O’Donnell, P.V., Symons, H.J., Chen, A.R., Leffell, M.S., Zahurak, M., Gooley, T.A., Piantadosi, S., Kaup, M., Ambinder, R.F., Huff, C.A., Matsui, W., Bolanos-Meade, J., Borrello, I., Powell, J.D., Harrington, E., Warnock, S., Flowers, M., Brodsky, R.A., Sandmaier, B.M., Storb, R.F., Jones, R.J., and Fuchs, E.J. (2008). HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 14, 641-650.
- Serafini, P., Mgebroff, S., Noonan, K., and Borrello, I. (2008). Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68, 5439-5449.
- Warlick, E.D., O’Donnell, P.V., Borowitz, M., Grupka, N., Decloe, L., Garrett-Mayer, E., Borrello, I., Brodsky, R., Fuchs, E., Huff, C.A., Luznik, L., Matsui, W., Ambinder, R., Jones, R.J., and Douglas Smith, B. (2008). Myeloablative allogeneic bone marrow transplant using T cell depleted allografts followed by post-transplant GM-CSF in high-risk myelodysplastic syndromes. Leuk Res 32, 1439-1447.
- Serafini, P., Borrello, I. & Bronte, V. (2006). Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16, 53-65.
- Serafini, P., Meckel, K., Kelso, M., Noonan, K., Califano, J., Koch, W., Dolcetti, L., Bronte, V. & Borrello, I. (2006). Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203, 2691-702.
- Matsui, W., Q. Wang, J. P. Barber, S. Brennan, B. D. Smith, I. Borrello, I. McNiece, L. Lin, R. F. Ambinder, C. Peacock, D. N. Watkins, C. A. Huff, and R. J. Jones. 2008. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 68:190-7.
- Mirmonsef, P., G. Tan, G. Zhou, T. Morino, K. Noonan, I. Borrello, and H. I. Levitsky. 2007. Escape from suppression: tumor-specific effector cells outcompete regulatory T cells following stem cell transplantation. Blood 111:2112-2121.
- Serafini P, Mgebroff S, Noonan K, Borrello I. (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res.(13):5439-49. PMID: 18593947
- Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I. (2006) Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 203(12):2691-702. Epub 2006 Nov 13. PMID 17101732
- Noonan K, Matsui W, Serafini P, Carbley R, Tan G, Khalili J, Bonyhadi M, Levitsky H, Whartenby K, Borrello I. (2005) Activated marrow-infiltrating lymphocytes effectively target plasma cells and their clonogenic precursors. Cancer Res.2026-34. PMID 1575340