Divergent Evolution of Malignant Subclones: A Balance Between Induced Aggressiveness and Intrinsic Drug Resistance in cutaneous T-cell lymphoma

Patients with leukemic cutaneous T-cell lymphoma (L-CTCL) have a poor prognosis due to development of drug-resistance and severe bacterial infections. Here, we use multimodal single-cell T-cell receptor and cellular indexing of transcriptomes and epitope sequencing (scTCR+CITE-seq) to show that most L-CTCL patients harbor multiple genetically distinct subclones that express an identical clonal antigen receptor but display distinct phenotypes and functional properties. These co-existing malignant subclones exhibit differences in tissue homing, metabolism, and cytokine expression, and respond differently to extrinsic factors like Staphylococcus (S.) aureus and cancer drugs. Indeed, while S. aureus toxins selectively enhance activation and proliferation of certain subclones, these responsive subclones are also the most intrinsically sensitive to cancer drugs when the stimuli are removed Whole transcriptome (GEX), T-cell receptor alpha-beta (TCRαβ), and surface protein (antibody derived tags; ADT) expression profiles of dissociated lesional skin separated into dermis and epidermis and matched peripheral blood mononuclear cells (PBMCs) from 23 leukemic cutaneous T-cell lympoma (L-CTCL) patients was analyzed by scTCR+CITE-seq. Also includes PBMCs cultured in the presence or absence of Staphylococcus aureus enterotoxins or the anti-cancer drug Romidepsin at several time points between 4 and 144 hours. For some patients only PBMCs were analyzed. *************************************************************** Raw files for human/patient samples were not submitted to GEO due to concerns about submitting personally identifiable sequence data for open access. ***************************************************************