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 IFNγ 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. Clin Cancer Res; 19(14); 3755–63. ©2013 AACR .