The Th9 axis reduces oxidative stress and promotes the survival of malignant T-cells in cutaneous T-cell lymphoma patients

Immune dysfunction is critical in pathogenesis of cutaneous T-cell lymphoma (CTCL). Few studies have reported abnormal cytokine profile and dysregulated T-cell functions during the onset and progression of certain types of lymphoma. However, the presence of IL-9 producing Th9 cells and their role in tumor cell metabolism and survival remain unexplored. With this clinical study, we performed multidimensional blood endotyping of CTCL patients before and after standard photo/chemo-therapy and revealed distinct immune hallmarks of the disease. Importantly, there was a higher frequency of "skin homing" Th9 cells in CTCL patients with early (T1, T2) and advanced-stage disease (T3, T4). However, advanced-stage CTCL patients had severely impaired frequency of skin-homing Th1 and Th17 cells, indicating attenuated immunity. Treatment of CTCL patients with standard photo/chemotherapy decreased the skin homing Th9 cells and increased the Th1 and Th17 cells. Interestingly, T-cells of CTCL patients express IL-9 receptor (IL-9R), and there was negligible IL-9R expression on T-cells of healthy donors. Mechanistically, IL-9/IL-9R interaction on CD3+ T-cells of CTCL patients and Jurkat cells reduced oxidative stress, lactic acidosis, and apoptosis and ultimately increased their survival. In conclusion, co-expression of IL-9 and IL-9R on T-cells in CTCL patients indicates the autocrine positive feedback loop of Th9 axis in promoting the survival of malignant T-cells by reducing the oxidative stress. Implications: The critical role of Th9 axis in CTCL pathogenesis indicates that strategies targeting Th9 cells might harbor significant potential in developing robust CTCL therapy.