LY01 Quantitative and functional alterations of B cells in cutaneous T-cell lymphomas

Abstract

Cutaneous T-cell lymphomas (CTCLs), particularly advanced mycosis fungoides (MF) and Sézary syndrome (SS), are characterized by profound immune dysfunction and susceptibility to infections. Beyond malignant T cells, the tumour microenvironment contributes to disease-associated immunosuppression. B cells, through antigen presentation and immunoregulatory cytokine production, represent an understudied component of the CTCL immune landscape. We aimed to comprehensively characterize the frequency, phenotype and functional properties of B cells in CTCL, with a specific focus on SS, across blood and skin compartments. We integrated multiparametric approaches including (i) cytometry by time of flight (CyTOF) on peripheral blood from 22 patients with SS, 24 patients with atopic dermatitis (AD), and 23 healthy donors; (ii) tissue microarray and immunohistochemistry analyses of skin biopsies from SS, MF and AD; (iii) single-cell transcriptomic data from independent cohorts and (iv) functional assays on purified B cells. Comparative analyses were used to assess B-cell abundance, immunophenotype, exhaustion markers and cytokine production. Patients with SS exhibited marked reduction of circulating and skin-infiltrating B cells compared with healthy donors and patients with AD, confirmed across platforms. Residual B cells in SS displayed a distinct exhausted and immunosuppressive phenotype, characterized by upregulation of inhibitory markers such as CD95 and LAG-3 and reduced expression of activation and migration markers including CD44. Cross-validation with independent single-cell RNA-sequencing datasets corroborated these findings. Functional assays further demonstrated a propensity of SS B cells towards interleukin-10 production, consistent with a regulatory B-cell-like profile. SS is associated with quantitative and qualitative alterations of the B-cell compartment in both blood and skin. The skewing towards an exhausted, interleukin-10-prone phenotype likely contributes to disease-associated immunosuppression. These findings highlight B cells as previously underappreciated players in CTCL pathobiology and suggest potential implications for immune dysregulation and therapeutic targeting in SS.