scRNA ‐Seq reveals anti‐lymphoma immune responses in mogamulizumab‐associated skin eruptions

BACKGROUND: Mogamulizumab is an anti-CCR4 therapeutic antibody approved for relapsed or refractory mycosis fungoides, Sézary syndrome and adult T-cell leukaemia/lymphoma. During treatment, a subset of patients develops a mogamulizumab-associated drug rash (MAR) that is associated with a better overall survival, but underlying mechanisms remain unclear. In addition, misinterpretation of MAR as cutaneous T-cell lymphoma (CTCL) progression can lead to unnecessary drug discontinuation. OBJECTIVES: To conduct a comprehensive molecular characterization of MAR. METHODS: We performed single-cell RNA sequencing of skin biopsies from 4 patients with MAR, compared to untreated erythrodermic CTCL (CTCL, n = 6) and healthy control (HC, n = 4) skin. RESULTS: CCR4 was primarily expressed in proliferating and non-proliferating malignant T-cell clones and FOXP3+ regulatory T cells in untreated CTCL, which were significantly decreased in MAR. The few residual malignant clones in MAR showed retained CCR4 expression, but decreases in the central memory markers SELL and CCR7, with upregulation of the MMP2 inhibitor TIMP2 and the tumour suppressor gene RUNX3, consistent with a more silenced immune phenotype. In parallel, polyclonal T cells in MAR lesions exhibited decreases in the exhaustion markers TIGIT and TOX, paralleled by upregulation of markers associated with cytotoxicity (GZMA) and anti-cancer properties (ZNF683). This increase in tumour suppressor and cytotoxicity genes potentially reflects an anti-lymphoma immune response within the MAR skin microenvironment. CONCLUSIONS: Our study provides novel insights into the molecular properties of residual malignant clones within MAR that appear silenced, surrounded by a putatively anti-tumor immune response.