Emerging evidence indicates that immune and inflammatory cytokine pathways promote the development and progression of lymphoma, however the molecular mechanisms are poorly defined. The TNF receptor superfamily member, HVEM (herpesvirus entry mediator;TNFRSF14) and the Ig superfamily protein, BTLA (B and T lymphocyte attenuator) form a novel signaling network that regulates lymphocyte activation and proliferation. Importantly, recent genetic analyses of human lymphomas and related hematologic malignancies revealed frequent somatic mutations in HVEM and BTLA that are associated with poor prognosis. Our research provides new evidence that somatic point mutations in HVEM identified in human lymphomas specifically alter ligand engagement, potentially affecting intrinsic NF?B survival pathways and immune regulatory mechanisms. We identified a novel transcriptional regulatory pathway that down modulates BTLA that may account for the suppression of BTLA expression in B and T-lymphoma cells. The HVEM-BTLA pathway, although well-recognized in host defense, is poorly defined in the context of cancer. The proliferation inhibiting functions and frequent somatic mutations suggest that the HVEM-BTLA pathway may serve as a check-point for the development and progression of hematologic malignancies. In this project, the molecular mechanisms of the dysregulation of the HVEM and BTLA pathway in human lymphoma lines will be determined. The affect of the HVEM-BTLA pathway is examined in mouse models of B cell malignancies. An array of antibody and receptor-based agonists and antagonists of the HVEM-BTLA related cytokines have been developed, and mice with null and conditional gene deletions in HVEM and BTLA are available to complement the results in human lymphoma cells. Together, these aims integrate molecular defects in the HVEM-BTLA pathways in human lymphoma with in vivo models to evaluate this pathway in the development and progression of lymphoma and leukemia, providing the rationale to therapeutically manipulate these pathways.
This project examines how cellular communication proteins called cytokines that normally control the growth of white blood cells change when their genes are mutated in lymphoma and leukemia. The experiments here will determine whether potential drugs directed at these cytokines halt the growth of lymphoma and leukemia.
|Colbeck, Emily J; Jones, Emma; Hindley, James P et al. (2017) Treg Depletion Licenses T Cell-Driven HEV Neogenesis and Promotes Tumor Destruction. Cancer Immunol Res 5:1005-1015|
|Desai, Pritesh; Abboud, Georges; Stanfield, Jessica et al. (2017) HVEM Imprints Memory Potential on Effector CD8 T Cells Required for Protective Mucosal Immunity. J Immunol 199:2968-2975|
|Šedý, John R; Balmert, M Olivia; Ware, Brian C et al. (2017) A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator. J Biol Chem 292:21060-21070|
|Ward-Kavanagh, Lindsay K; Lin, Wai Wai; Šedý, John R et al. (2016) The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity 44:1005-19|
|Scarzello, Anthony J; Jiang, Qun; Back, Timothy et al. (2016) LT?R signalling preferentially accelerates oncogenic AKT-initiated liver tumours. Gut 65:1765-75|
|Koh, Mei Yee; Gagea, Mihai; Sargis, Timothy et al. (2016) A new HIF-1?/RANTES-driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF in mice. Hepatology 63:1576-91|
|Šedý, John; Bekiaris, Vasileios; Ware, Carl F (2015) Tumor necrosis factor superfamily in innate immunity and inflammation. Cold Spring Harb Perspect Biol 7:a016279|
|Lau, E; Sedy, J; Sander, C et al. (2015) Transcriptional repression of IFN?1 by ATF2 confers melanoma resistance to therapy. Oncogene 34:5739-48|
|Gommerman, Jennifer L; Browning, Jeffrey L; Ware, Carl F (2014) The Lymphotoxin Network: orchestrating a type I interferon response to optimize adaptive immunity. Cytokine Growth Factor Rev 25:139-45|
|Bekiaris, Vasileios; Šedý, John R; Ware, Carl F (2014) Mixing Signals: Molecular Turn Ons and Turn Offs for Innate ?? T-Cells. Front Immunol 5:654|
Showing the most recent 10 out of 16 publications