IL-13 as a novel growth factor in CTCL

In this issue of Blood, Geskin et al report that interleukin-13 (IL-13) acts as an autocrine growth factor in cutaneous T-cell lymphoma (CTCL) and that simultaneous antibody-based neutralization of IL-13 and IL-4 inhibits in vitro proliferation of CTCL cells.¹ 

CTCL is composed of 2 closely related, yet clinically very distinct, subtypes of mycosis fungoides (MF) and erythroderma typically associated with circulating Sézary cells (Sézary syndrome [SS]). Despite extensive investigation, the pathogenesis of CTCL, both MF and erythroderma/SS, remains poorly understood. Consequently, the therapies remain predominantly empirical, and not directly based on pathobiology of the malignant cells. Recent identification in CTCL of point mutations of the PLCG1 and other cell signaling-related genes²  may accelerate introduction of targeted therapies in this disorder.

The growing body of mostly circumstantial evidence indicates that cytokine signaling plays a critical role in CTCL.^3-5  Although for most of the disease course, the CTCL cells depend on cytokines for their survival and proliferation, at the late stage they seem to become cytokine independent but continue to display persistent activation of cytokine signaling pathways such as signal transducer and activator of transcription 3 (STAT3) and STAT5, presumably due to genetic alterations within the signaling proteins. Although early on, T helper 1 (Th1)–type cytokines such as IL-2 and IL-15 dominate in MF, Th2 cytokines such as IL-4 gradually begin to prevail relatively soon, due to the loss of the IL-12–responsive STAT4 expression in some cases.⁵  There is also evidence of the CTCL cells’ Th17 differentiation,^6,7  likely driven, or augmented, by bacterial and fungal infections, frequently seen in the advanced stages of CTCL characterized by marked immunosuppression, seemingly due in part to expression of IL-10.⁴  Whereas IL-17 expression has been found in MF lesions,⁶  other investigators identified IL-26 as being dominant in the Th17-biased CTCL cells.⁷  IL-32 has also been suggested to play a role of an autocrine growth factor in CTCL, in particular in the advanced disease.⁸  Surprisingly, IL-32 expression correlated with expression of the Th1 cytokine interferon γ but not the Th2 cytokines. Finally, CTCL cells have been found to produce the pruritus-promoting, inflammatory cytokine IL-31.⁹ 

The above findings clearly indicate that CTCL lesions contain multiple cytokines and their number, type, and exact composition are dynamic and disease-stage dependent.^4,5  This cytokine diversity is associated with plasticity of the CTCL cells,⁴  reflected by their ability to acquire various Th phenotypes, depending on the stimuli provided by the cytokines, antigen-presenting cells, and other factors present in their direct milieu. Consequently, most of the CTCL skin lesions, in particular at the earlier stages of the disease, are expected to contain a large number of various cytokines and phenotypically diverse subpopulations of the CTCL cells.

Recent studies have also implicated IL-13 in pathogenesis of CTCL. This Th2-type cytokine is functionally closely related to IL-4 by sharing a common receptor composed of the IL-4Rα and IL-13Rα1 chains, with both cytokines activating STAT6 as the major cell-signaling transmitter. Guenova et al reported on the strong bias of leukemic Sézary cells as well as nonmalignant cells from the same SS syndrome patients toward the Th2 phenotype, marked by the IL-4 and IL-13 secretion.¹⁰  The CTCL cell-derived, IL-4– and IL-13–containing supernatants promoted conversion of the normal T cells from the Th1 to the Th2 phenotype, and neutralizing antibodies to IL-4 and IL-13 restored the Th1 phenotype. In turn, Wolk et al demonstrated that IL-13 plays a role in the susceptibility of CTCL patients to the bacterial infections by downregulating expression of antibacterial proteins.⁷  The current study¹  complements these observations by providing evidence that IL-13 directly stimulates growth of Sézary cells and acts in these cells as an autocrine growth factor. Although IL-13 inhibition by a neutralizing antibody markedly suppressed growth of the Sézary cells, the inhibition was even more profound when an IL-4–neutralizing antibody was also added. Interestingly, the IL-13 expression was seen not only in the leukemic Sézary cells but also at all stages of MF, with the most robust expression at the advanced stages of the disease.

The emerging important role of IL-13 in CTCL^1,7,10  makes this cytokine an attractive target for a therapeutic intervention, in particular if IL-4 is targeted simultaneously. As described by Geskin et al,¹  inhibition of the IL-4 and IL-13 binding to their common receptor by an anti–IL-4Rα monoclonal antibody dupilumab had shown therapeutic efficacy in asthma and atopic dermatitis, 2 Th2-type disorders. Given the availability of highly potent small-molecule Jak inhibitors, targeting the Jak1 and Tyk2 kinases associated with the IL-4Rα/IL-13Rα1 complex is also a consideration. In principle, STAT6 may also be an attractive target given the relative specificity of its activation by IL-4 and IL-13. However, clinical-grade STAT6 inhibitors are still under development. It could be argued that the selective targeting of IL-13/IL-4–mediated cell activation as a single therapeutic modality should be the most effective in erythroderma/SS and the MF cases with the strongest Th2 bias. It may, however, be insufficient in other cases and its effects may be transient even in the responding patients, unless combined with other therapeutic approaches.

In summary, identification of IL-13 as an important factor in CTCL expands our understanding of the pathogenesis of this complex lymphoproliferative disorder and has potential therapeutic implications.