TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL

High-throughput TCR sequencing can accurately diagnose and discriminate CTCL cells in skin. Discriminating taste for CTCL Cutaneous T cell lymphoma (CTCL) is a potentially debilitating disease, but early stages resemble rashes of less dangerous inflammatory skin diseases. Now, Kirsch et al. report that high-throughput TCR sequencing (HTS) can be used to distinguish CTCL from benign inflammatory disease by identifying T cell clones. This diagnostic was more sensitive and specific than the current standard of care and was also able to determine therapeutic response and identify early recurrence. The authors then used HTS to gain insight into CTCL pathogenesis, reporting that the malignancy derived from mature T cells that may have a specialized niche in the skin. Early diagnosis of cutaneous T cell lymphoma (CTCL) is difficult and takes on average 6 years after presentation, in part because the clinical appearance and histopathology of CTCL can resemble that of benign inflammatory skin diseases. Detection of a malignant T cell clone is critical in making the diagnosis of CTCL, but the T cell receptor γ (TCRγ) polymerase chain reaction (PCR) analysis in current clinical use detects clones in only a subset of patients. High-throughput TCR sequencing (HTS) detected T cell clones in 46 of 46 CTCL patients, was more sensitive and specific than TCRγ PCR, and successfully discriminated CTCL from benign inflammatory diseases. HTS also accurately assessed responses to therapy and facilitated diagnosis of disease recurrence. In patients with new skin lesions and no involvement of blood by flow cytometry, HTS demonstrated hematogenous spread of small numbers of malignant T cells. Analysis of CTCL TCRγ genes demonstrated that CTCL is a malignancy derived from mature T cells. There was a maximal T cell density in skin in benign inflammatory diseases that was exceeded in CTCL, suggesting that a niche of finite size may exist for benign T cells in skin. Last, immunostaining demonstrated that the malignant T cell clones in mycosis fungoides and leukemic CTCL localized to different anatomic compartments in the skin. In summary, HTS accurately diagnosed CTCL in all stages, discriminated CTCL from benign inflammatory skin diseases, and provided insights into the cell of origin and location of malignant CTCL cells in skin.