Divergent Evolution of Malignant Subclones Maintains a Balance Between Induced Aggressiveness and Intrinsic Drug Resistance in T Cell Cancer

Evolution and outgrowth of drug-resistant cancer cells is a common cause of treatment failure. 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 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. Consequently, although divergent evolution of malignant subclones drives aggressiveness, adaptability and drug-resistance, by removing extrinsic stimuli and mapping malignant subclones, we can expose inherent vulnerabilities that can be exploited in the treatment of these cancers.