Single-cell RNA sequencing characterization of mogamulizumab-associated drug rash in cutaneous lymphoma patients

Summary: Abstract Body: Mogamulizumab is an anti-CCR4 therapeutic antibody approved for relapsed or refractory mycosis fungoides and for Sézary syndrome. 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 CTCL progression can lead to unnecessary drug discontinuation. We performed single-cell RNA sequencing of skin biopsies from 4 patients with MAR, in comparison to untreated erythrodermic CTCL (eCTCL, n=6) and healthy controls (HC, n=4). We found a strongly expanded malignant clone in all eCTCL skin samples (range 29%-79% of all T cells), whereas numbers were significantly lower or even absent in MAR (range 0%-39% of all T cells). As expected, we found a significant decrease in CCR4+ T cells in MAR, together with reduced numbers of FOXP3+ regulatory T cells, compared to both eCTCL and HC samples, in line with the strong pro-inflammatory microenvironment within MAR lesions. Remaining malignant clones in MAR samples showed decreases in the central memory markers SELL and CCR7, as well as the TSLP-receptor component CRLF2 and the lymphoma marker KIR3DL2. We have previously demonstrated that increased B cell counts within the tumor microenvironment are associated with advancing CTCL. Importantly, we found decreases in the B-cell attracting chemokine CXCL13 within MAR lesions, paralleled by reduced numbers of CD19+ B cells. Within polyclonal bystander T cells, we found decreased levels of the exhaustion marker TIGIT in MAR compared to eCTCL, potentially reflecting a more tumor-permissive microenvironment in the latter. In sum, our study provides insights into molecular properties of residual malignant clones within MAR, which show an overall attenuated phenotype. Shannon Meledathu¹, Agata Kurowski¹, Malini P. Naidu¹, Jónas Adalsteinsson¹, Sumanth Chennareddy¹, Natalia Alkon², Lauren R. Port¹, Emry R. Cohenour¹, Grace Christensen¹, Johannes Griss², Constanze Jonak², Patrick M. Brunner¹ 1. Icahn School of Medicine at Mount Sinai, New York, NY, United States. 2. Medizinische Universitat Wien, Vienna, Vienna, Austria. UV Biology/Injury and Non-melanoma Cancers