Saturday, September 7, 2024
9/7/2024
Mycosis Fungoides (MF) is a clonal disorder of skin-resident memory T cells and is the most common form of cutaneous T-cell lymphoma (CTCL). In the early stages of MF, T cells reside primarily in the skin and only a few circulate in peripheral blood. However, in a significant number of patients the disease progresses within 10 years with tumor cells spreading to other sites of the body leading to a fatal outcome. Diagnosis of MF is difficult to establish, especially in the early stages because the symptoms and histologic features mimic other benign inflammatory dermatoses and specific markers for malignant lymphocytes are lacking; consequently, MF may be misdiagnosed and treated inappropriately resulting in poorer clinical outcomes. We have recently shown that malignant T lymphocytes from early- and advanced-stage MF skin lesions produce high levels of cytokine IL-13 and, significantly, that they also express the IL-13-specific receptor IL-13Ra1, unlike healthy human T cells. Further, we demonstrated that IL-13 acts as an autocrine factor for tumor lymphocytes and implicated IL-13 signaling via IL-13Rα1 and the Signal Transducer and Activator of Transcription-6 (STAT-6). Based on these results, our central hypothesis is that IL-13Rα1 expression by malignant T lymphocytes in early-stage MF skin lesions is a prospective marker for the early diagnosis of MF. In this proposal we will test our hypothesis by investigating the correlation between IL-1Rα1 expression, T cell malignancy and patient characterization. We will employ Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) to measure immunophenotypes and transcriptomes simultaneously in thousands of individual cells from a large heterogeneous population such as a patient biopsy. Parallel high-resolution profiling of the T cell immune repertoire will identify the expanded malignant T cell clones directly in MF patient skin samples. We aim to identify IL-13-specific pathways in malignant IL-13Rα1+ T cells from early-stage MF skin lesions by comparison with adjacent unaffected skin, healthy control skin, and skin affected by benign inflammatory dermatosis. In a second focus, multicolor immunohistochemical methods will be used on banked samples from the PROCLIPI repository to assess expression of IL13Rα1 by T cells for a retrospective correlation with the associated clinical data obtained longitudinally over the years. This work will reveal the association between IL13Rα1 expression by T cells and MF tumorigenesis and progression. Successful completion will provide a framework for evaluating IL13Rα1 as a candidate biomarker that may be developed into a diagnostic test based on multicolor immunohisto- chemistry/immunofluorescence that would be suitable for the clinical setting.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
