Our Science – Hurwitz Website
Arthur Andrew Hurwitz, Ph.D.
Recent work cited in the news:
NIH study identifies gene that suppresses cell's immune activation
Our lab studies T cell tolerance to antigens relevant to cancer and autoimmune disease. We are interested in understanding how 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. Our over-arching hypothesis is that a successful anti-tumor immune response is dependent on manipulation of immune suppression in the tumor microenvironment as well as the avidity of the T cell response. There are 2 on-going projects that address these issues: (1) a melanoma-based project, where we are studying T cell responses to a melanoma antigen, TRP-2 and (2) a prostate cancer-based project, where we are studying the influence of the tumor microenvironment on T cell responses to tumor antigens.
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. We are studying how T cell avidity correlates with susceptibility to tolerance induction. This work is being performed in collaboration with Dr. Enzo Bronte (Univ of Padova), Dr. Viktor Umansky (Univ. of Heidelberg), and Dr. Mary Jo Turk (Dartmouth Medical College).
Project 2: Tumor Microenvironment Influences 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. 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. 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 and acquisition of suppressive function in the prostate tumor. While a peptide-pulsed DC vaccine was capable of delaying tolerization, co-transfer of the tumor-specific TcR-II cells was capable of preventing T cell tolerance and inhibiting tumor growth. More recently, we have identified a population of plasmacytoid-like dendritic cells which tolerize T cells. Expression of the transcription factor FOXO3A is critical for this tolerogenic function. Most strikingly, a similar population of plasmacytoid dendritic cells exists in human prostate cancer, and these cells also rely FOXO3A expression for their immune-suppressive function. These findings implicate FOXO3A as a novel target for enhancing immunotherapy to cancer. This work is being performed in collaboration with Dr. Giorgio Trinchieri (NCI), Dr. Stefan Ambs (NCI), and Dr. Hideo Yagita (Juntendo University).
If you are interested in research opportunities in the Tumor Immunity and Tolerance Section, please contact Dr. Hurwitz at firstname.lastname@example.org.
This page was last updated on 5/21/2014.