Maria Castro
Maria Castro
Professor
mariacas@umich.edu

Research Description

Development of immunotherapies for primary and metastatic brain cancer: from basic immunobiology mechanisms to translational immune-therapeutics. Tumor immune-microenvironment: its role in tumor progression and response to therapeutics. Cross talk between cancer cells and hematopoietic stem/progenitor cells. Mechanisms affecting the migration of immune cells from peripheral lymphoid organs to the tumor microenvironment

My research program covers the areas of cancer immunology, the tumor microenvironment, signaling via pattern recognition receptors, innate immunity, role of cancer derived ligands at modulating the maturation of the myeloid hematopoietic stem cell lineage, and the development of immune mediated and targeted gene therapeutic approaches for the treatment of cancers -both primary brain tumors (i.e., glioblastoma multiforme, GBM) and also metastatic brain cancer (e.g., melanoma, lung cancer, breast, colon and prostate). GBM is the most aggressive primary brain tumor; it has a five year survival rate of <5%. Attempts at eliciting a clinically relevant anti-GBM immune response in brain tumor patients have met with limited success, due to the brain's immune privileged status, tumor immune evasion, and a paucity of dendritic cells (DCs) within the central nervous system. Recently, we have uncovered a novel pathway for the activation of an effective anti-GBM immune response and therapy which involvesthe high-mobility-group box 1 (HMGB1) protein, an alarmin released from dying tumor cells, which acts as an endogenous ligand for Toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs.

Using a combined immunotherapy/conditional cytotoxic approach that utilizes adenoviral vectors (Ad) expressing Fms-like tyrosine kinase 3 ligand (Flt3L) and Herpes Virus type 1 thymidine kinase (HSV1-TK) delivered into the tumor mass (Ali et al, Cancer Research, 2005), we demonstrated that cytotoxic T cells mediate both tumor regression and immunological memory. Infiltration of dendritic cells (DCs), and other immune cells, into the GBM microenvironment, clonal expansion of antitumor T cells, and induction of an effective anti-GBM immune response were TLR2 dependent. My group demontrated that the endogenous ligand responsible for TLR2 signaling on tumor-infiltrating DCs is HMGB1. Increased levels of HMGB1 were detected in the serum of tumor-bearing Ad-Flt3L/Ad-HSV1TK (+GCV)-treated mice. HMGB1 was also released from melanoma, small cell lung carcinoma, and glioma cells treated with radiation or temozolomide, indicating the universality of this mechanism. Administration of either glycyrrhizin (a specific HMGB1 inhibitor) or anti-HMGB1 immunoglobulins to tumor-bearing mice treated with Ad-Flt3L and Ad-TK, abolished therapeutic efficacy, demonstrating the critical role played by HMGB1-mediated TLR2 signaling to elicit tumor regression (Curtin et al, PLoS Medicine, 2009, 6 (1), e10). We are aiming to design and develop small molecules, HMGB1 agonists to be used as adjuvants for the treatment of solid cancers.

As an extension of these new data, my team has embarked on a research project which aims to uncover the molecular and cellular signaling cascades triggered by pattern recognition receptor ligands released by tumor cells. Our data indicates that these tumor derived ligands bind to pattern recognition receptors present on bone marrow derived hematopoietic stem cells (HSCs) and -as a consequence- they halt their maturation, thus inducing the accumulation of immature immunosuppressive cells, i.e., myeloid derived suppressor cells (MDSCs). We anticipate these studies will uncover previously unknown anti-cancer therapeutic targets, i.e., using small molecules and small interfering RNA technologies, aimed at modulating the maturation of MDSCs. These studies should also direct us to new research areas on the interphase between cancer and hematopoietic stem cell biology.

Education

11/1988-8/1990 Senior Research Fellow, Laboratory of Molecular Endocrinology, Department of Biochemistry and Physiology, University of Reading, P O Box 228, Reading, RG6 2AJ, U.K.
4/1986-11/1988 Fogarty International Visiting Research Fellow, Laboratory of Neurochemistry and Neuro-immunology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20892, USA
6/1982-5/1986 Postgraduate Research Fellowship Granted by Medical Research Council, Buenos Aires, Argentina, Institute for Endocrine Studies, School of Medicine, National University of Argentina at La Plata
3/1983-12/1986 M.Sc. - Education Technology, School of Biological Sciences, National University of La Plata, Argentina
9/1981- 4/1986 Ph.D. Biochemistry, School of Biological Sciences, National University of La Plata
12/1979-8/1981 M.Sc. Biochemistry, School of Biological Sciences, National University of La Plata
3/1973-11/1979 B.Sc. Hons (1st Class) Chemistry, School of Biological Sciences, National University of La Plata 3/1973-11/1979