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.