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 cells accumulate in the blood and give rise to widespread skin inflammation. Patients have intense pruritus, increased immunoglobulin E (IgE), and decreased T-helper (T-H)-1 responses, and most die from infection. Depleting malignant T cells while preserving normal immunity is a clinical challenge. L-CTCL has been variably described as a malignancy of regulatory, T(H)2 and T(H)17 cells. Experimental Design: We analyzed phenotype and cytokine production in malignant and benign L-CTCL T cells, characterized the effects of malignant T cells on 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 T(H)2 cytokines. Remaining benign T cells were also strongly T(H)2 biased, suggesting a global T(H)2 skewing of the T-cell repertoire. Culture of benign T cells away from the malignant clone reduced T(H)2 and enhanced T(H)1 responses, but separate culture had no effect on malignant T cells. Coculture of healthy T cells with L-CTCL T cells reduced IFN gamma production and neutralizing antibodies to interleukin (IL)-4 and IL-13 restored T(H)1 responses. In patients, enhanced T(H)1 responses were observed following a variety of treatment modalities that reduced malignant T-cell burden. Conclusions: A global T(H)2 bias exists in both benign and malignant T cells in L-CTCL and may underlie the infectious susceptibility of patients. T(H)2 cytokines from malignant cells strongly inhibited T(H)1 responses. Our results suggest that therapies that inhibit T(H)2 cytokine activity, by virtue of their ability to improve T(H)1 responses, may have the potential to enhance both anticancer and antipathogen responses. (C) 2013 AACR.