Single-cell RNA sequencing analyses of primary cutaneous B-cell disorders reveal distinct molecular patterns consistent with clinical behavior

Abstract

Cutaneous B-cell lymphomas (CBL) comprise a diverse group of diseases with variable clinical course and prognosis. The cellular and molecular mechanisms underlying the pathogenesis of CBL remain ill-defined. Here we performed single-cell RNA sequencing combined with B-cell and T-cell receptor sequencing in three distinct CBL entities. In contrast to benign cutaneous pseudolymphomas and healthy skin, each CBL variant contained a single dominant B-cell clone. In marginal zone lymphoproliferative disorder (MZLPD), expanded clones generally showed terminal differentiation along a physiological trajectory towards plasma cells and displayed transcriptomic profiles indistinguishable from the benign polyclonal bystander B-cells. Follicle center lymphoma (FCL) clones also exhibited a canonical B-cell marker profile but consisted of more homogeneous populations of proliferating and non-proliferating germinal center (GC) B-cell-like phenotypes. In the most aggressive CBL, diffuse large B-cell lymphoma, leg type (DCBCL-LT), cells revealed multiple non-physiological marker profiles as well as aberrant proliferative activity beyond conventional GC-like cells. Fibroblasts in MZLPD, FCL and pseudolymphomas, but not DLBCL-LT, expressed the classical chemotactic chemokine CXCL13. These data suggest that in cutaneous B-cell disorders other than DLBCL-LT, physiological immune circuits are primarily operative, consistent with their overall indolent behavior.