Psoralen plus UVA (PUVA) is an effective therapy for mycosis fungoides (MF), the skin-limited variant of cutaneous T cell lymphoma (CTCL). In low-burden patients, PUVA reduced or eradicated malignant T cells and induced clonal expansion of CD8+ T cells associated with malignant T cell depletion. High-burden patients appeared to clinically improve but large numbers of malignant T cells persisted in skin. Clinical improvement was linked to turnover of benign T cell clones but not to malignant T cell reduction. Benign T cells were associated with the Th2-recruiting chemokine CCL18 before therapy and with the Th1-recruiting chemokines CXCL9, CXCL10, and CXCL11 after therapy, suggesting a switch from Th2 to Th1. Inflammation was correlated with OX40L and CD40L gene expression; immunostaining localized these receptors to CCL18-expressing c-Kit+ dendritic cells that clustered together with CD40+OX40+ benign and CD40+CD40L+ malignant T cells, creating a proinflammatory synapse in skin. Our data suggest that visible inflammation in CTCL results from the recruitment and activation of benign T cells by c-Kit+OX40L+CD40L+ dendritic cells and that this activation may provide tumorigenic signals. Targeting c-Kit, OX40, and CD40 signaling may be novel therapeutic avenues for the treatment of MF.
Pablo Vieyra-Garcia, Jack D. Crouch, John T. O’Malley, Edward W. Seger, Chao H. Yang, Jessica E. Teague, Anna Maria Vromans, Ahmed Gehad, Thet Su Win, Zizi Yu, Elizabeth L. Lowry, Jung-Im Na, Alain H. Rook, Peter Wolf, Rachael A. Clark
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Yu Z, Vieyra-Garcia P, Benezeder T, Crouch JD, Kim IR, O'Malley JT, Devlin PM, Gehad A, Zhan Q, Gudjonsson JE, Sarkar MK, Kahlenberg JM, Gerard N, Teague JE, Kupper TS, LeBoeuf NR, Larocca C, Tawa M, Pomahac B, Talbot SG, Orgill DP, Wolf P, Clark RA |
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Immunological Reviews | 2023 |