The overlap of skin and blood T-cell clones in early-stage mycosis fungoides

Abstract

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma that initially presents in the skin but can progress to involve blood and extracutaneous sites with significant mortality in advanced stages.1 Even in early stages and in the absence of blood involvement, changes in the blood T-cell receptor (TCR) repertoire have been observed in patients with MF.2-5 Indeed, the detection of a monoclonal TCR gene rearrangement by polymerase chain reaction (PCR) in the blood of patients with early-stage MF has been linked to worse overall survival,6 lower response rates,7 and a shorter time to systemic treatment (TTST).8 The impact of dominant blood T-cell clones in early MF becomes more complex if the relationship of the detectable clones in the blood and skin is interrogated. A prior study, using PCR, demonstrated that identical, but not discordant, dominant clones in blood and skin of patients with MF increased the likelihood of disease progression.9 Although prior work has explored the significance of dominant blood T-cell clones in the prognosis of MF,1,9-12 PCR-based assays do not allow for a full characterization of TCR sequences and cannot adequately compare T-cell repertoires in the skin and blood. Here, we used high-throughput TCR sequencing to interrogate skin and blood T-cell repertoires in a large cohort of patients with early-stage MF over the course of their disease. We aimed to determine the relationship of blood and skin T-cell repertories and reassess the impact of dominant blood T-cell clones on selected outcome end points in early-stage MF. Sixty patients with a confirmed histopathological diagnosis of MF without blood involvement were enrolled at Jefferson’s Cutaneous Lymphoma Clinic (supplemental Tables 1-4). Each patient was staged according to the criteria by Olsen et al,13 and 50 of 60 patients (83%) had early-stage MF (IA-IIA; supplemental Tables 1-3). We used high-throughput TCR sequencing to interrogate the TCRβ complementarity determining region 3 (CDR3) sequences in blood and lesional skin biopsies of enrolled patients (Adaptive Biotechnologies). ImmunoSEQ Analyzer provided T-cell repertoire overlap metric (Morisita index) and diversity measure (Simpson clonality score).3,14-16 TTST was calculated as the time from initial diagnosis to the initiation of the first systemic therapy. Using ClonoSEQ criteria to establish dominancy,17 we found that 17 of 60 patients (28%) had a dominant T-cell clone in blood. Of these 17 patients, 3 (18%) had an identical dominant T-cell clone in both skin and blood, and 14 (82%) had a discordant dominant clone identified in the skin and blood (supplemental Table 1). We compared the TTST in patients with a dominant blood clone, regardless of whether they were identical to or discordant with the skin clone, with TTST in patients without a dominant blood clone