Psoralen Plus UVA Induces Local IFN Production and Antitumor Responses in Cutaneous T-Cell Lymphoma

View Large Image Figure ViewerDownload Hi-res image Download (PPT) Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas derived from neoplastic T cells in the skin (Dummer et al., 2021Dummer R. Vermeer M.H. Scarisbrick J.J. Kim Y.H. Stonesifer C. Tensen C.P. et al.Cutaneous T cell lymphoma.Nat Rev Dis Primers. 2021; 7: 61Google Scholar). Mycosis fungoides (MF) is the most common subtype of CTCL and typically presents with inflammatory patches and plaques. Phototherapy is an effective skin-directed therapy for CTCL, with response rates of up to 90% in early-stage disease (Olsen et al., 2016Olsen E.A. Hodak E. Anderson T. Carter J.B. Henderson M. Cooper K. et al.Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: a consensus statement of the United States Cutaneous Lymphoma Consortium.J Am Acad Dermatol. 2016; 74: 27-58Google Scholar). The most common phototherapy modalities are psoralen plus UVA (PUVA) and narrow-band UVB (nbUVB). PUVA was the first phototherapy approved for CTCL, and a recent meta-analysis suggests overall response rates and adverse effect profiles similar to those of nbUVB (Phan et al., 2019Phan K. Ramachandran V. Fassihi H. Sebaratnam D.F. Comparison of narrowband UV-B with psoralen-UV-A phototherapy for patients with early-stage mycosis fungoides: a systematic review and meta-analysis.JAMA Dermatol. 2019; 155: 335-341Google Scholar). As such, PUVA remains the initial treatment of choice for many cutaneous oncologists. Multiple mechanisms have been proposed for the clinical effects of PUVA, including direct DNA damage by psoralen and induction of apoptosis in neoplastic T cells (Johnson et al., 1996Johnson R. Staiano-Coico L. Austin L. Cardinale I. Nabeya-Tsukifuji R. Krueger J.G. PUVA treatment selectively induces a cell cycle block and subsequent apoptosis in human T-lymphocytes.Photochem Photobiol. 1996; 63: 566-571Google Scholar). In their recent article in Journal of Investigative Dermatology, Yu et al., 2023Yu Z. Vieyra-Garcia P. Benezeder T. Crouch J.D. Kim I.R. O’Malley J.T. et al.Phototherapy restores deficient type I interferon production and enhances antitumor responses in mycosis fungoides [epub ahead of print].J Invest Dermatol. 2023; (accessed XXX)https://doi.org/10.1016/j.jid.2023.06.212Google Scholar report that PUVA induces type I IFN responses in the skin, leading to enhancement of antitumor immune responses and tumor clearance in patients with MF (Figure 1).“The results of this study by Yu et al. demonstrate a previously unknown connection between phototherapy and augmentation of interferon responses in a subset of MF patients.” “The results of this study by Yu et al. demonstrate a previously unknown connection between phototherapy and augmentation of interferon responses in a subset of MF patients.” Yu et al., 2023Yu Z. Vieyra-Garcia P. Benezeder T. Crouch J.D. Kim I.R. O’Malley J.T. et al.Phototherapy restores deficient type I interferon production and enhances antitumor responses in mycosis fungoides [epub ahead of print].J Invest Dermatol. 2023; (accessed XXX)https://doi.org/10.1016/j.jid.2023.06.212Google Scholar first studied gene expression profiles in skin biopsies from patients with stages IA–IIB MF. This analysis revealed significant downregulation of type I IFN transcripts in MF skin compared with that in healthy controls. Immunofluorescence staining of skin samples similarly revealed a relative deficit of epidermal IFN-α in MF. Conversely, negative regulators of type I IFN production (IRF2, IFI35) were upregulated in MF and correlated with the number of malignant T cells in the skin. As such, the authors postulate that malignant T cells may contribute to the observed suppression of endogenous IFN response in MF. To evaluate whether PUVA modulates the suppressed IFN response in MF, the investigators next compared IFN expression in skin biopsies before and after treatment. IFNA1 and IFNB1 transcripts were restored to levels similar to those in healthy controls after 12 weeks of PUVA. The increased IFN expression observed after treatment with PUVA also correlated with ULBP2 expression, a known marker of epithelial IFN production, suggesting that keratinocytes are the key cell type responsible for IFN production in response to PUVA. To further characterize the source of IFN production, the investigators performed a series of in vitro experiments. Treatment of keratinocytes with UVA alone or PUVA induced significant expression of IFNA1 and IFNB1. This effect appears to be mediated by IFN-κ, a keratinocyte-derived IFN that has previously been shown to drive photosensitivity and overproduction of type I IFNs in cutaneous lupus (Sarkar et al., 2018Sarkar M.K. Hile G.A. Tsoi L.C. Xing X. Liu J. Liang Y. et al.Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa.Ann Rheum Dis. 2018; 77: 1653-1664Google Scholar). Indeed, CRISPR-targeted deletion of IFN-κ in keratinocytes abrogated the production of IFNA1 and IFNB1 in response to PUVA. To investigate the downstream effects of PUVA-induced IFN production, Yu et al., 2023Yu Z. Vieyra-Garcia P. Benezeder T. Crouch J.D. Kim I.R. O’Malley J.T. et al.Phototherapy restores deficient type I interferon production and enhances antitumor responses in mycosis fungoides [epub ahead of print].J Invest Dermatol. 2023; (accessed XXX)https://doi.org/10.1016/j.jid.2023.06.212Google Scholar evaluated clinical responses as measured by disease severity scores and malignant T-cell counts. Although induction of IFN responses was notably heterogeneous, post-treatment IFN levels were associated with a significant reduction in Composite Assessment of Index Lesion Severity score. Further analysis revealed that patients with effective tumor clearance (>90% clearance of the malignant clone) tended to have strong induction of IFN responses after PUVA, whereas patients with poor-to-intermediate tumor clearance had little change in IFN responses after PUVA. Of note, the increased IFN response observed in patients with effective tumor clearance was associated with a significant increase in CD8+ T-cell genes and activation markers as well as recruitment of new benign T-cell clones into the skin. Taken together, these data suggest that PUVA-induced IFN production promotes effective antitumor immunity by driving CD8+ T-cell recruitment and effector function in affected skin lesions. The results of this study by Yu et al., 2023Yu Z. Vieyra-Garcia P. Benezeder T. Crouch J.D. Kim I.R. O’Malley J.T. et al.Phototherapy restores deficient type I interferon production and enhances antitumor responses in mycosis fungoides [epub ahead of print].J Invest Dermatol. 2023; (accessed XXX)https://doi.org/10.1016/j.jid.2023.06.212Google Scholar demonstrate a previously unknown connection between phototherapy and augmentation of IFN responses in a subset of patients with MF. Although the mechanistic portion of this study largely focused on the direct effects of phototherapy on keratinocytes, further analysis using single-cell and spatial transcriptomic technologies will be useful to elucidate the potential interactions between phototherapy and other cells in the tumor microenvironment, including myeloid cells, regulatory T cells, and malignant T cells themselves. Interestingly, an earlier report demonstrated that PUVA may also be effective at clearing peripheral blood disease in patients with leukemic CTCL (Raphael et al., 2011Raphael B.A. Morrissey K.A. Kim E.J. Vittorio C.C. Rook A.H. Psoralen plus ultraviolet A light may be associated with clearing of peripheral blood disease in advanced cutaneous T-cell lymphoma.J Am Acad Dermatol. 2011; 65: 212-214Google Scholar). This raises the possibility that skin-directed PUVA may have systemic immune–potentiating effects beyond the local induction of IFNs described in this study by Yu et al., 2023Yu Z. Vieyra-Garcia P. Benezeder T. Crouch J.D. Kim I.R. O’Malley J.T. et al.Phototherapy restores deficient type I interferon production and enhances antitumor responses in mycosis fungoides [epub ahead of print].J Invest Dermatol. 2023; (accessed XXX)https://doi.org/10.1016/j.jid.2023.06.212Google Scholar, possibly through the production of other cytokines such as TNF-α (Vowels et al., 1992Vowels B.R. Cassin M. Boufal M.H. Walsh L.J. Rook A.H. Extracorporeal photochemotherapy induces the production of tumor necrosis factor-alpha by monocytes: implications for the treatment of cutaneous T-cell lymphoma and systemic sclerosis.J Invest Dermatol. 1992; 98: 686-692Google Scholar). Because PUVA is primarily used as a palliative treatment in patients with late-stage CTCL, a better understanding of these mechanisms may facilitate the use of this therapy for more advanced cases. Overall, the findings described in this study are highly complementary to the existing body of literature on interferogenic therapies in CTCL, including systemic pegylated IFN-α (Spaccarelli and Rook, 2015Spaccarelli N. Rook A.H. The use of interferons in the treatment of cutaneous T-cell lymphoma.Dermatol Clin. 2015; 33: 731-745Google Scholar) and topical toll-like receptor agonists such as imiquimod and resiquimod (Rook et al., 2015Rook A.H. Gelfand J.M. Wysocka M. Troxel A.B. Benoit B. Surber C. et al.Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma [published correction appears in Blood 2015;126:2765].Blood. 2015; 126: 1452-1461Google Scholar). For this reason, the IFN pathway remains an attractive target for current and future therapies in CTCL, and multimodal treatment strategies aimed at boosting IFN responses merit further investigation. AHR serves as a consultant for TLR Bio and a lecturer for Mallinckrodt. The remaining author states no conflict of interest. Phototherapy Restores Deficient Type I IFN Production and Enhances Antitumor Responses in Mycosis FungoidesJournal of Investigative DermatologyPreviewTranscriptional profiling demonstrated markedly reduced type I IFN gene expression in untreated mycosis fungoides (MF) skin lesions compared with that in healthy skin. Type I IFN expression in MF correlated with antigen-presenting cell–associated IRF5 before psoralen plus UVA therapy and epithelial ULBP2 after therapy, suggesting an enhancement of epithelial type I IFN. Immunostains confirmed reduced baseline type I IFN production in MF and increased levels after psoralen plus UVA treatment in responding patients. Full-Text PDF