Research Interests:Exploiting TLR signaling in T cells for enhanced anti-tumor activity (Project 1)
Supported by R01CA140917 and by P20RR021970
T cell-based therapies for cancer in the form of adoptive T cell transfer (ACT) or cancer vaccines can kill tumors expressing immunodominant tumor antigens (TA). However, this process allows the escape of tumor cells expressing poorly immunogenic or subdominant TAs. These cells can reestablish the tumor and metastasize, ultimately killing the host. We are currently addressing several of the most significant hurdles in developing T cell-based immunotherapy and propose innovative ways to circumvent these challenges.
We have genetically modified human T cells to express a tumor-specific TCR and to produce the TLR5 ligand. We are testing the hypothesis that tumor-reactive T cells will generate potent and long-lived antitumor activity by co-stimulating both tumor-specific T cells and antigen presenting cells at the tumor site via production of TLR ligands within the tumor microenvironment. In these experiments, we use a physiologically relevant human-to-mouse model that allows a detailed evaluation of the in vivo responses of tumor-specific CD8 T cells against melanoma tumors in the brain.
We are also focused on defining the signaling pathway through which TLR2-MyD88 signals within tumor-reactive CD8 T cells potentiate activation to a poorly immunogenic tumor antigen. Our current indicate that the costimulatory effects of MyD88 signaling in T cells is regulated in large part by the mammalian target of rapamycin (MTOR). Furthermore, research efforts have led to examine the three specific miRNAs which appear to regulate MyD88 signaling in T cells.
Pattern recognition receptors and T-cell leukemia progression (Project 2)
Supported by a grant from the Leukemia and Lymphoma Society
Our long-term objective for this project is to understand the role of dysregulated TLR-MyD88-IRAK signaling in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and to develop novel diagnostic, prognostic, and therapies to treat patients. Recent studies highlight a previously unappreciated role for pattern recognition receptor (PRR) signaling (i.e. toll-like receptors, TLR) on T-cells and their effects on survival and proliferation. PRRs can bind exogenous molecules derived from pathogens as well as endogenous ligands released from stressed or dying cells. Our published reports on primary T-cells and our preliminary data using T-cell leukemia lines and samples from patients with T-ALL indicate that direct stimulation of PRRs enhances cell proliferation and survival.
We seek to understand the prevalence and physiological significance of PRR signaling in neoplastic T-cells. We are also examining the therapeutic efficacy of inhibiting TLR-MyD88-IRAK signaling with or without chemotherapy in vivo. For these studies we use patient-derived T-ALL cells transferred into the immune-compromised Nod-Scid mice.
Grants & Contracts:
Supported by R01CA140917, P20RR021970, Leukemia and Lymphoma Society, and the University of Maryland Greenebaum Cancer Center
Morrison C, Baer MR, Zandberg DP, Kimball A, Davila E. Effects of Toll-like receptor signals in T-cell neoplasms. Future Oncol. 2011 Feb;7(2):309-20.
Geng D, Zheng L, Srivastava R, Velasco-Gonzalez C, Riker A, Markovic SN, Davila E. Amplifying TLR-MyD88 signals within tumor-specific T cells enhances antitumor activity to suboptimal levels of weakly immunogenic tumor antigens. Cancer Res. 2010 Oct 1;70(19):7442-54. Epub 2010 Aug 31.
Geng D, Zheng L, Srivastava R, Asprodites N, Velasco-Gonzalez C, Davila E. When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector function. Blood. 2010 Nov 4;116(18):3494-504. Epub 2010 Aug 9.
Davila E, Geng D, Sanchez-Perez L, Riker A. Immunotherapy Highlights. Immunotherapy. 2009 Nov;1(6):921-4.
Davila E, Kolls J. A "Toll" for Th17 cell expansion. J Leukoc Biol. 2010 Jul;88(1):5-7.
Asprodites N, Zheng L, Geng D, Velasco-Gonzalez C, Sanchez-Perez L, Davila E. Engagement of Toll-like receptor-2 on cytotoxic T-lymphocytes occurs in vivo and augments antitumor activity. FASEB J. 2008 Oct;22(10):3628-37.
Zheng L, Asprodites N, Keene AH, Rodriguez P, Brown KD, Davila E. TLR9 engagement on CD4 T lymphocytes represses gamma-radiation-induced apoptosis through activation of checkpoint kinase response elements. Blood. 2008 Mar 1;111(5):2704-13.
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