Is blocking IL‐4 receptor alpha beneficial for patients with mycosis fungoides or Sézary syndrome?

Abstract

Dear Editor, Mycosis fungoides (MF) and Sézary syndrome (SS), a representative of cutaneous Tcell lymphoma (CTCL), are regarded as a T helper 2 (Th2)type disease. Th2 cytokines are detected in MF skin lesions and SS tumor cells produce interleukin (IL)4, IL5 and IL13.1 Thymic stromal protein, a mediator of Th2 immune response, is strongly expressed by keratinocytes in MF/SS as well as in atopic dermatitis (AD).2 Th2dominant microenvironment is beneficial for tumor cells because Th1 cells augment antitumor immune responses. IL4 is also important for inducing and activating regulatory T cells, myeloidderived suppressor cells, and M2 macrophages, all of which are involved in tumor development. Dupilumab, a human monoclonal antibody against IL4 receptor (R) alpha blocks signaling of IL4 and IL13, improving severe dermatitis in AD. Considering Th2dominant microenvironment in MF/SS, the drug had been expected to be effective for controlling clinical symptoms. There have been 19 CTCL cases treated with dupilumab in ten English papers (Table 1). In 13 cases, previous diagnosis was AD or eczema, while in six cases, dupilumab was used offlabel for CTCL. In most cases, skin symptoms initially improved, followed by its worsening. Only three cases (No. 14, 16, 17) showed improvement of skin lesions. Interestingly, progression of SS has been frequent, considering the rarity of the disease. Even in a case with improvement of skin lesions (No. 17), increase in SS cells was reported, suggesting that dupilumab could cause progression of blood disease. The high frequency of SS may also have come from the fact that SS is more difficult than MF to distinguish from AD. All authors concluded that patients with the diagnosis of AD had been actually MF/SS before treatment. Considering the cumulative number of cases treated with dupilumab, oncogenic conversion by the treatment is very unlikely. Interleukin4 is abundant in tumor microenvironment and most types of tumor cells express increased levels of IL4R.