Our Science – Hurwitz Website

Arthur Andrew Hurwitz, Ph.D.

Laboratory of Molecular Immunoregulation Head, Tumor Immunity and Tolerance Group Investigator CIP, LMI, CCR, National Cancer Institute Building 567, Room 211 Frederick, MD 21702 Phone:   301-846-5443 Fax:   301-846-7350 E-Mail:   hurwitza@ncifcrf.gov

Biography

Dr. Hurwitz received his Ph.D. from the Albert Einstein College of Medicine in 1994, where he studied the role of the blood-brain barrier in HIV infection of the central nervous system (CNS) with Drs. Bill Lyman and Joan Berman. He continued his training at UC Berkeley as a Postdoc with Dr. Jim Allison. His studies were on the role of T cell costimulatory signals in modulating anti-tumor and autoimmune responses. In 1999, Dr. Hurwitz was appointed Assistant Professor of Microbiology and Immunology and Urology at SUNY Upstate Medical University in Syracuse, NY. His research program moved to the CCR in 2003, where he continues to study T cell tolerance to antigens relevant in anti-tumor immunity and autoimmune disease in animal models.

Research

One of the unique features of the immune system is its ability to distinguish between self- and non-self-antigens. As T cells develop in the thymus, most T cells with specificity for self-antigens are eliminated (aka, negative selection) and T cells that recognize foreign antigens associated with self-MHC receive a signal to be exported to the periphery (aka, positive selection), However; some T cells with specificity for self-antigen/self-MHC are retained and reside in the periphery as anergic (unresponsive) or ignorant (god forbid). These cells are vital to understanding the immune response to cancer, which arises from self-tissues expressing predominantly self-antigens, and to understanding autoimmune diseases, where self-reactive T cells contribute to pathology of self-tissues.

Our lab studies T cell tolerance to antigens relevant to cancer and autoimmune disease. We are interested in understanding how these self-reactive T cells exist in the peripheral immune system and what signals are required to activate them. We propose that there is a unique link between immunity to tumors and autoimmune disease and that a greater understanding of this relationship will lead to more successful treatments of both diseases. There are 3 on-going projects that address these issues: (1) a melanoma project, where we are studying T cell responses to a melanoma antigen, TRP-2, (2) a prostate cancer project, where we are studying T cell tolerance in a murine model of primary prostate cancer, and (3) a new project studying the role of inflammation in prostate carcinogenesis.

Project 1: T Cell Avidity Plays a Critical Role in Determining Tumor Immunity and Autoimmunity

We have previously reported that sensitization to a TRP-2 (180-188) minimal epitope only induces a weak T cell response, but in combination with CTLA-4 blockade, TRP-2 sensitization is capable of inducing only localized autoimmune depigmentation. However, combining the TRP-2 vaccine and CTLA-4 blockade with a GM-CSF-expressing, amelanotic tumor vaccine resulted in enhanced recruitment of APCs to draining lymph nodes and enhanced immunity to the B16 tumors. Thus, blocking CTLA-4-mediated inhibitory signals is sufficient to lower the threshold for inducing autoimmune depigmentation, but eliciting an anti-tumor response requires recruitment of APCs and expanding the magnitude of the T cell response to this minimal epitope.

We are currently using novel TRP-2-specific TcR transgenic mice to study the influence of T cell avidity on tumor immunity and autoimmunity. Mice were generated that bear transgenes encoding TcRs that recognize a common immunodominant TRP-2 epitope. TcR V gene usage differs, but more importantly, the T cells differ in their functional avidity. This work is being performed in collaboration with Dr. Enzo Bronte (Univ of Padova).

Project 2: Tumor Growth and Microenvironment Influence T Cell Tolerance to Tumor Antigens

Our previous studies have taken advantage of the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, developed by our long-term collaborator, Dr. Norm Greenberg (Fred Hutchinson Cancer Ctr). TRAMP mice carry an SV40 T Antigen (TAg) transgene under the transcriptional control of the rat probasin promoter which directs expression to the prostatic epithelium. Using this model, we demonstrated that CTLA-4 blockade, in combination with a GM-CSF-expressing vaccine, elicits a potent anti-tumor response and reduces tumor incidence and tumor grade in TRAMP mice. We are now using TRAMP mice to study T cell reactivity to prostate tumor antigens, using TAg as a model antigen. We are employing two different strains of TcR transgenic mice, which bear monoclonal T cells with specificity for either MHC class I- (TcR-I) or class II-restricted (TcR-II) epitopes of TAg. We recently reported that transfer of naive TcR-I cells into TRAMP mice results in rapid expansion in the periphery, followed by tolerization in the prostate tumor. While a peptide-pulsed DC vaccine was capable of delaying tolerization, the immunosuppressive microenvironmnet of the TRAMP tumor ultimately tolerizes the T cells. We are currently studying the cross-talk between tumor-specific CD4+ and CD8+ T cells. In addition, we are charcterizing the role of a population of prostate-resident dendritic cells which may contribute to T cell tolerization. This work is being performed in collaboration with Dr. Giorgio Trinchieri (NCI) and Dr. Protul Shrikant (Roswell Park Cancer Inst).


Project 3: Chronic Prostatic Inflammation Promotes Carcinogenesis

Like other cancers, prostate cancer may have an inflammatory component to its etiology, yet this has not been directly tested. We have preliminary data that suggest that in two model systems, inflammatory processes may initiate transformation of the mouse prostate. We are using genetic and 'infectious' models to study the role of inflammation in prostate cancer development. This project is being performed in collaboration with Dr. Bill Farrar (NCI).

If you are interested in research opportunities in the Tumor Immunity and Tolerance Section, please contact Dr. Hurwitz @ hurwitza@ncifcrf.gov.

This page was last updated on 9/17/2008.