TH2 Cytokines from Malignant Cells Suppress TH1 Responses and Enforce a Global TH2 Bias in Leukemic Cutaneous T-cell Lymphoma

Purpose: In leukemic cutaneous T-cell lymphoma(L-CTCL), malignant T cellsaccumulate in the blood and give rise to widespread skin inflammation. Patients have intense pruritus, increased immunoglobulin E(IgE), and decreased T-helper ( TH )-1 responses, and most die from infection. Depleting malignant T cellswhile preserving normal immunity is a clinical challenge. L-CTCL has been variably described as a malignancyof regulatory, TH 2 and TH 17 cells. Experimental Design: We analyzed phenotype and cytokine production in malignantand benign L-CTCL T cells, characterized the effects of malignant T cellson healthy T cells, and studied the immunomodulatory effects of treatment modalities in patients with L-CTCL. Results: Twelve out of 12 patients with L-CTCL overproduced TH 2 cytokines. Remaining benign T cellswere also strongly TH 2 biased, suggesting a global TH 2 skewing of the T-cell repertoire. Culture of benign T cellsaway from the malignantclone reduced TH 2 and enhanced TH 1 responses, but separate culture had no effect on malignant T cells. Coculture of healthy T cellswith L-CTCL T cellsreduced IFNγ production and neutralizing antibodies to interleukin (IL)-4 and IL-13 restored TH 1 responses. In patients, enhanced TH 1 responses were observed following a variety of treatment modalities that reduced malignant T-cell burden. Conclusions: A global TH 2 bias exists in both benign and malignant T cellsin L-CTCL and may underlie the infectious susceptibility of patients. TH 2 cytokines from malignantcells strongly inhibited TH 1 responses. Our results suggest that therapies that inhibit TH 2 cytokine activity, by virtue of their ability to improve TH 1 responses, may have the potential to enhance both anticancer and antipathogen responses. Clin Cancer Res; 19(14); 3755–63. ©2013 AACR .