Dr Coukos laboratory focuses on three areas that evolve around the overarching theme of tumor microenvironment:
Tumor immune surveillance and tolerance
The Coukos lab discovered that immune surveillance mechanisms are spontaneously activated in select patients with ovarian cancer and that their activation is heralded by the presence of T cells infiltrating tumor islets (intratumoral T cells). These predict indolent clinical behavior and long survival (New England Journal of Medicine 2003). The lab also identified important mechanisms that promote tumor cell recognition by providing costimulatory signals to cytotoxic lymphocytes, or tumor immune tolerance through regulatory T cells. We are currently characterizing mechanisms of tumor immune evasion, including the role of tumor endothelium in regulating homing of effector T cells in ovarian cancer; the role of vascular leukocytes in expanding Treg and killing effector T cells; and the role of chemokines in recruiting select populations of T cells in the tumor microenvironment. Furthermore, we are characterizing the function of tumor-infiltrating effector T cells and we are exploring their potential for adoptive lymphocyte therapy. Lastly, we are seeking to identify biomarkers that will predict positive response to adoptive lymphocyte therapy or vaccine therapy.
Immune-vascular interactions
The Coukos lab discovered that dendritic cell precursors infiltrating tumors are transformed into endothelial-like cells in the tumor microenvironment under the influence of vascular endothelial growth factor (VEGF), the master regulator of angiogenesis. These cells were named vascular dendritic cells or vascular leukocytes and were detected at high frequency both in a mouse model of ovarian cancer generated in my lab as well as in human ovarian cancers. We showed that vascular leukocytes can assemble de novo blood vessels and are recruited to the tumors by beta defensins, antimicrobial peptides produced by tumor cells. This work generates novel therapeutic targets, as we have recently shown that depletion of these vascular dendritic cells induces dramatic decrease in tumor growth. Furthermore, for the first time it raises important questions on the effect of bone marrow support during cytotoxic chemotherapy in ovarian cancer. To learn more about tumor vasculature, we have developed and optimized immunohistochemistry-guided laser capture microdissection followed by RNA amplification and transcriptional profiling to discover the molecular profile of tumor vasculature in situ. We discovered a large number of novel tumor vascular markers. We are currently generating antibodies against novel transmembrane tumor vascular targets. We are interested in developing vascular therapy based on antibodies or redirected T cells expressing chimeric immunoreceptors.
Microenvironment editing by tumor cells
This line of research tests the hypothesis that genomic alterations driving malignant transformation also edit the tumor microenvironment, inducing tumor-promoting inflammation, angiogenesis and immune tolerance. We are taking genomic and proteomic approaches to characterize common genomic alterations in ovarian cancer and define their effect on genes implicated in editing the tumor microenvironment, regulating angiogenesis and immune response.
Recent Publications:
J.R. Conejo-Garcia, F. Benencia, M.C. Courreges, P.A. Gimotty, E. Khang, R.J. Buckanovich, K.A. Frauwirth, L. Zhang, D. Katsaros, K. Sclienger, C.B. Thompson, B. Levine, G. Coukos. LETAL promotes the survival and induces expansion of CD28(-) antitumor T cells through the NKG2D immunoreceptor in ovarian carcinoma. Cancer Res. 64:2175-82, 2004.
J.R. Conejo-Garcia, F. Benencia, M.C. Courreges, E. Kang, A. Mohamed-Hadley, R.J. Buckanovich, D. Holtz, A. Jenkins, H. Na, L. Zhang, D.S. Wagner, D.Katsaros, R. Caroll, G. Coukos. Tumor-infiltrating dendritic cell precursors recruited by beta-defensin contribute to vasculogenesis under the influence of VEGF. Nature Medicine, 10:942-9, 2004.
T.J. Curiel, G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-Hogan, J.R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I.Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M.L. Disis, K. Knuston, L. Chen, W. Zou. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine, 10:950-8, 2004
L. Zhang, N. Yang, R.J. Buckanovich, J. Huang, S. Liang, C. Vezzani, A. O'Brien-Jenkins, J. Wang, M. Renee Gerrero, M. C. Courreges, S. Fracchioli, A. Medina, D. Katsaros, B. L Weber, G. Coukos. Transcriptional Coactivator, Drosophila Eyes Absent Homolog 2 (Eya2), is Upregulated in Human Epithelial Ovarian Cancer and Promotes Tumor Growth. Cancer Res. 65:925-32, 2005.
Lotze MT, Wang E, Marincola FM, Hanna N, Bugelski PJ, Burns CA, Coukos G, (10 authors), Weinstein JN, Whiteside TL. Workshop on Cancer Biometrics: Identifying Biomarkers and Surrogates of Cancer in Patients: A Meeting Held at the Masur Auditorium, National Institutes of Health. J. Immunother., 28:79-119, 2005.
Conejo-Garcia, J.R., R.J. Buckanovich, F. Benencia, M.C. Courreges, R.G. Carroll, G. Coukos. Vascular Leukocytes Contribute to Ovarian Tumor Vascularization. Blood, 105:679-81, 2005.
G. Coukos, F. Benencia, R. Buckanovich J.R. Conejo-Garcia. The role of dendritic cell precursors in tumour vasculogenesis. Br. J. Cancer. 92:1182-7, 2005.
F. Benencia, G.Coukos. T regulatory cell depletion can boost DC-based Vaccines. Cancer Biol Ther. 4:218-223, 2005.
F. Benencia, M.C. Courréges, J.R. Conejo-García, R.J. Buckanovich, L. Zhang, R.G. Carroll, M.A. Morgan, G. Coukos. Oncolytic HSV Exerts Direct Antiangiogenic Activity in Ovarian Carcinoma. Human Gen Ther. 16:765-778, 2005.
F. Benencia, M.C. Courrèges, J.R. Conejo-García, N. Fraser, G. Coukos. Dendritic Cell-derived Interferon-inducible Chemokines Induce Tumor Infiltration by Immune Effector Cells Following HSV Oncolytic Therapy. Molec. Ther. 12:789-802 2005.
G. Coukos, J.R. Conejo-Garcia, T.C. Wu. Immunotherapy for Gynecologic Malignancies. Exp. Op. Biol. Ther. 5:1193-210, 2005.
M.C. Courrèges, F. Benencia, J.R. Conejo-García, L. Zhang, G. Coukos. Preparation of apoptotic tumor cells with replication-incompetent HSV augments the efficacy of dendritic cell vaccines. Cancer Gene Ther. 13:182–193, 2006.
R.J. Buckanovich, Sasaroli, D., Jenkins-O'Brien, A., Botbyl, J., Conejo-Garcia, J. R., Benencia, F., Liotta, L. A., Gimotty, P. A., and Coukos, G. Use of Immuno-LCM to identify the in situ expression profile of cellular constituents of the tumor microenvironment. Cancer Biol. Ther, 5:635-642, 2006.
L. Zhang, J. Huang, N. Yang, L. Shun, A. Barchetti, A. Giannakakis, M. Massobrio, A. O’Brien-Jenkins, D. Katsaros, R. Butzow, P. Gimotty, B.L. Weber, G. Coukos. Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota as a biomarker and potential oncogene in ovarian carcinoma. Cancer Res. 66:(9)635-42, 2006.
Buckanovich, R. J., Sasaroli, D., O'Brien-Jenkins, A., Botbyl, J., Hammond, R., Katsaros, D., Sandaltzopoulos, R., Liotta, L. A., Gimotty, P. A., and Coukos, G. Tumor vascular proteins as biomarkers in ovarian cancer. J Clin Oncol 25, 852-61, 2007..
Coukos, G., Conejo-Garcia, J. R., Buckanovich, R., and Benencia, F. Vascular leukocytes: a population with angiogenic and immunossuppressive properties highly represented in ovarian cancer. Adv Exp Med Biol 590, 185-93, 2007.
Czerniecki, B. J., Koski, G. K., Koldovsky, U., Xu, S., Cohen, P. A., Mick, R., Nisenbaum, H., Pasha, T., Xu, M., Fox, K. R., Weinstein, S., Orel, S. G., Vonderheide, R., Coukos, G., DeMichele, A., Araujo, L., Spitz, F. R., Rosen, M., Levine, B. L., June, C., and Zhang, P. J. ). Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res 67, 1842-52, 2007.
Greshock, J., Nathanson, K., Martin, A. M., Zhang, L.,
Coukos, G., Weber, B. L., and Zaks, T. Z. Cancer cell lines
as genetic models of their parent histology: analyses based
on array comparative genomic hybridization. Cancer Res 67,
3594-600, 2007.
Hung, C. F., Tsai, Y. C., He, L., Coukos, G., Fodor, I.,
Qin, L., Levitsky, H., and Wu, T. C. Vaccinia virus
preferentially infects and controls human and murine
ovarian tumors in mice. Gene Ther 14, 20-9, 2007.
Rolaki, A., Coukos, G., Loutradis, D., DeLisser, H. M.,
Coutifaris, C., and Makrigiannakis, A. Luteogenic hormones
act through a vascular endothelial growth factor-dependent
mechanism to up-regulate alpha 5 beta 1 and alpha v beta 3
integrins, promoting the migration and survival of human
luteinized granulosa cells. Am J Pathol 170, 1561-72, 2007.