IL-35: A Key Immunosuppressive Driver in Mycosis Fungoides Modulated by Phototherapy

Overview

Mycosis fungoides is the most common type of skin lymphoma. It develops when certain white blood cells (T cells) grow abnormally in the skin, causing red, scaly, or itchy patches. The disease is often treated with phototherapy, a light-based treatment that can control symptoms in early stages. This study looked at a protein called interleukin-35 (IL-35), which normally helps regulate the immune system but can also suppress the body's ability to fight cancer. The investigators aimed to determine if IL-35 levels are higher in patients with mycosis fungoides and whether phototherapy can change those levels. The study enrolled 16 patients with mycosis fungoides and compared them to 16 healthy people. Blood samples and small skin biopsies were taken before and after phototherapy. The study found that IL-35 levels were significantly higher in patients than in healthy people. After phototherapy, IL-35 levels dropped back to normal. These results suggest that phototherapy not only treats skin lesions directly but also helps restore immune balance by lowering IL-35. IL-35 may become a useful marker to monitor disease activity and treatment response in patients with mycosis fungoides.

Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma and is characterized by progressive immune dysregulation. Early disease often shows a T helper 1 (Th1) profile, while advanced stages shift toward an immunosuppressive T helper 2 (Th2) environment that promotes tumor persistence. Interleukin-35 (IL-35), a recently described member of the IL-12 cytokine family, has emerged as a potent immunosuppressive cytokine. It contributes to tumor growth by suppressing anti-tumor T-cell responses, expanding regulatory T cells, and fostering angiogenesis. Elevated IL-35 levels have been reported in several malignancies, including MF, but its behavior under therapeutic intervention has not been well defined. Phototherapy, including psoralen plus ultraviolet A (PUVA) and narrowband ultraviolet B (NB-UVB), remains a cornerstone treatment for early-stage MF. Beyond its direct cytotoxic effects on malignant T cells, phototherapy exerts broad immunomodulatory actions on the cutaneous cytokine milieu. Prior studies have shown normalization of cytokines such as IL-15 following phototherapy, suggesting that its benefits extend beyond lesion clearance to restoration of immune balance. This prospective interventional cohort study was designed to evaluate whether IL-35 levels in serum and skin tissue are altered by phototherapy in MF patients. Sixteen patients with histologically confirmed MF and sixteen matched healthy controls were enrolled. IL-35 was measured at baseline in both groups and again after phototherapy in patients. The study demonstrated that IL-35 levels were significantly elevated in MF patients compared to controls, and that both serum and tissue IL-35 declined after phototherapy, normalizing to control levels. These findings suggest that phototherapy may correct the immunosuppressive environment characteristic of MF, and that IL-35 could serve as a biomarker for disease activity and treatment response.