TGF-B-Signaling in Anti-Tumor T Cells in CNS

Thorsten R. Mempel, Ph.D.

Massachusetts General Hospital

Center for Immunology and Inflammatory Diseases
Funded in December, 2008: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Cellular Imaging in Living Mice May Help Reveal How Brain Tumor Cells Resist Immune Attacks

This study will use multiphoton intravital microscopy in a mouse brain tumor model to understand how these tumors evade the immune system.

Research indicates that adaptive immune cells, called cytotoxic T lymphocytes (CTLs), initially recognize and attack brain tumors, but the tumors quickly develop the means to resist these immune attacks.  Evidence of initial immune responses, however, has stimulated efforts to design immunotherapies that can strengthen immune responses against the tumors.  CTLs from the blood of cancer patients are efficient at killing tumor cells, yet CTLs found within the tumors are frequently functionally inactive.  This suggests that events occurring within the tumor environment impair their function. 

Two immune cell populations suspected of counteracting CTL attacks of brain tumors are regulatory T cells and myeloid-derived suppressor cells (MDSCs).  The investigators hypothesize that the regulatory T cells inhibit CTLs from attacking tumors by inducing an innate immune cell type of the brain, called microglia, (and possibly newly recruited blood-borne inflammatory cells) to become MDSCs.  The investigators will use multiphoton intravital microscopy to study the interplay of CTLs, regulatory T cells, MDSCs and tumor cells.  This technique, which they helped to champion for the study of the immune system, shows the migration and interaction of individual immune cells in a living animal.

ABSTRACT

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TGF-B-Signaling in Anti-Tumor T Cells in CNS

It is now well recognized that malignant growths, including those of the central nervous system (CNS), induce responses by the innate and the adaptive immune system.  Emergence of clinically apparent tumors is thought to result from the induction of tumor antigen-specific immunologic tolerance.  Interference with tumor tolerance mechanisms is a promising strategy for novel therapies based on harnessing the power of the immune system to treat cancer.  Despite the immune-privileged status of the CNS, tumors of the brain are demonstrably also confronted with anti-tumor T cell responses, which are however usually insufficient to reject the tumors.

The goal of this project is to improve our understanding of how the immune system interfaces with malignant tumors of the CNS in order to design more effective, targeted immunotherapy of brain tumors.  Specifically, we will investigate how the interaction of tumor-reactive cytotoxic T lymphocytes (CTL) with myeloid antigen-presenting cells (APC) derived from microglia and blood-borne monocytes in the tumor environment as well as their effector function against tumor cells is controlled by tumor-reactive regulatory T cells (Treg).  We hypothesize that Treg induce a suppressive phenotype in tumor-associated microglia and monocytes (TAM) and that TAM in turn inhibit the function of tumor-infiltrating CTL through cognate interactions in a TGF--dependent fashion.

To test this hypothesis we will: (1) adapt a mouse tumor model for the study of antigen-specific anti-tumor T cell responses and develop an multiphoton intravital microsopy (MP-IVM)-based approach to study the migratory behavior of CTL, TAM, and tumor cells through direct dynamic observation in the brains of living anaesthetized mice; (2) characterize their interactive behavior and how it is affected by the presence or absence of Treg; and (3) examine if TGF--signals are involved in the transmission of suppressive information from Treg to CTL via TAM.

If successful, this study will provide important mechanistic insight into the cellular events underlying tumor tolerance.  This will allow for the design of innovative therapeutic strategies in the treatment of brain tumors by clarifying the role of a precise molecular target (TGF--receptor) on a defined cell population (CTL) and will make it possible to take advantage of evolving technologies for the targeted delivery of immunomodulatory agents.

INVESTIGATOR BIOGRAPHIES

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Thorsten R. Mempel, Ph.D.

Thorsten R. Mempel, Ph.D., is an assistant professor in medicine at Harvard Medical School and a principal investigator of the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital.  He holds an M.D. and a Ph.D. in medical physiology from the University of Munich Medical School, Germany.  He was a resident in pediatric surgery before beginning his research training at the Institute for Surgical Research in Munich, where he developed microscopic imaging techniques for the visualization of immune cell migration in inflammation in living anaesthetized mice. 

During his postdoctoral fellowship in the laboratory of Dr. Ulrich von Andrian he pioneered the use of multiphoton intravital microscopy for the study of T cell interactions with antigen-presenting cells in lymph nodes during the initiation of immune responses.  The work of Dr. Mempel’s own laboratory now focuses on the mechanisms that regulate the execution of T cell immune responses in peripheral tissues.  For this his group uses mouse models of malignant disease to study the migration and interaction of various immune cell subsets with each other and with cancer cells during anti-tumor responses. 

The results of their efforts are hoped to contribute to the development of innovative immunotherapies of cancer by identifying critical cellular and molecular targets for therapeutic intervention aimed to induce immunological rejection of cancer in human patients.