Chronic inflammation is frequently noted as a major risk factor in the development of cancer. Cutaneous T cell lymphoma (CTCL) is a debilitating cancer marked by an expansion of malignant T cells in the skin and whose etiology remains unknown. CTCL patient tumor samples often show markers of inflammation such as elevated levels of STAT3 phosphorylation and IL-17 production. This observation implicates T helper 17 cells (Th17 cells), which require the transcription factor STAT3 for differentiation and which secrete the pro-inflammatory cytokine IL-17, as the cells of origin for this disease. T cells isolated from CTCL patients show signs of chronic antigenic stimulation and lesion sites are often enriched for antigen presenting cells highlighting a potentially critical role for T cell receptor (TCR) signaling in tumorigenesis. Given that Th17 cell differentiation in the skin has been recently shown to rely on exposure to specific bacterial species, bacterial antigens may be crucial mediators of this disease. The fact that antibiotic treatment given to CTCL patients to eliminate Staphylococcus aureus infections often leads to a noticeable clinical improvement further points to a potential role for bacteria in the genesis of this disease. This project aims to determine the role of antigenic signaling and the contribution of the skin microbiome to CTCL pathogenesis. To accomplish this, we have generated a mouse model in which a hyperactive mutant STAT3 (STAT3C) is expressed specifically in T cells. These mice develop a lymphoproliferative disease with features highly reminiscent of CTCL including skin lesions and enrichment of IL-17 producing T cells in the skin. Our preliminary experiments show that crossing this mouse model onto a background lacking endogenous TCR signaling ameliorates disease progression. Further, preliminary results indicate that rederiving this line in germ-free conditions yields a similar delay of disease onset. The proposed experiments will investigate the precise role for antigenic signaling in this model and use gnotobiotic methods, informed by skin microbiome analysis of our model and CTCL patients, to identify the microbial species most important for disease initiation. In doing so, this study will potentially yield broad insights into the genesis of T cell malignancies and highlight novel therapeutic targets.
The experiments detailed in this study have significant implications for cancer immunology and may uncover mechanisms of lymphoma initiation and progression, potentially improving outcomes of patients with this disease. This proposal examines the role of immune cell signaling and skin bacterial flora in the development of Cutaneous T Cell Lymphoma (CTCL), a debilitating disease with no cure. By uncovering mechanisms critical for tumor formation and identifying specific bacterial species that contribute to disease, this research may uncover novel therapeutic targets and disease markers that can lead to the development of future treatments and diagnostic tools for CTCL and lymphomas more broadly.
|Yang, Lu; Fanok, Melania H; Mediero-Munoz, Aranzazu et al. (2018) Augmented Th17 Differentiation Leads to Cutaneous and Synovio-Entheseal Inflammation in a Novel Model of Psoriatic Arthritis. Arthritis Rheumatol 70:855-867|
|Fanok, Melania H; Sun, Amy; Fogli, Laura K et al. (2018) Role of Dysregulated Cytokine Signaling and Bacterial Triggers in the Pathogenesis of Cutaneous T-Cell Lymphoma. J Invest Dermatol 138:1116-1125|