612 Treg depletion syndrome: Skin inflammation unleashed by ADCC depleting biologics

T cell depleting antibodies used for the treatment of cutaneous T cell lymphoma, including alemtuzumab (αCD52) and mogamulizumab (αCCR4), utilize an IgG1 constant region and deplete T cells via antibody dependent cellular cytotoxicity (ADCC), which requires accessory cells (NK, neutrophils) that are rare in skin. These therapies deplete T cells in blood and purge recirculating T cells from skin, but do not deplete skin resident memory T cells (TRM). We observed new onset eczematous dermatitis in a subset of alemtuzumab treated leukemic CTCL (L-CTCL) patients that was associated with an 89% depletion of FOXP3+ Tregs from skin, suggesting Treg are a recirculating cell type. Studies in healthy human skin confirmed 72% of cutaneous Tregs were recirculating, compared to 19% of proinflammatory/conventional CD4+ T cells. We now report an L-CTCL patient who developed erythrodermic psoriasis following treatment with alemtuzumab. TCR sequencing found clearance of the malignant T cell clone from blood and skin and a new polyclonal expansion of resident memory T cells that were present before treatment. Gene expression profiling of skin biopsies demonstrated reduced expression of Sezary associated genes (CCR4, CCL5, CX3CR1, CD70) and increased psoriasis associated genes (IL-17A, IL-1B, CXCL1,5,9) after alemtuzumab treatment. Multiplex immunostaining demonstrated a 89% depletion of Treg from skin after treatment and the presence of expanded CD8+CD103+ TRMand IL-17A producing cells in the epidermis. The patient was subsequently treated with secukinumab (αIL-17A) with clearance of his erythrodermic psoriasis and was successfully transplanted. Depleting monoclonal antibodies can be effective therapies for L-CTCL but those that deplete by ADCC are less effective at depleting in skin limited disease (mycosis fungoides) and can induce inflammatory dermatoses by depleting recirculating Treg from skin. Depleting biologic medications intended for the treatment of skin limited CTCL should be formulated using constant regions that do not depend on ADCC for T cell depletion.