Search

Cutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (T H 2) cell-immune gene programs by malignant CTCL cells and modeling of the tumor microenvironment to support their survival. We identified MHC-II + fibroblasts and dendritic cells that can maintain T H 2 cell-like tumor cells. CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. Finally, we validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL., Competing Interests: Competing interests: In the past 3 years, S.A.T. has received remuneration for scientific advisory board membership from Sanofi, GlaxoSmithKline, Foresite Labs and Qiagen. She is a co-founder of and holds equity in Transition Bio and Ensocell. From 8 January 2024, she has been a part-time employee of GlaxoSmithKline. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Cutaneous T-cell lymphomas (CTCL) are characterized by focal infiltration of malignant T cell clones in solitary skin lesions. Many CTCL patients experience an indolent disease, but some progress to advanced disease with high fatality. We hypothesized that natural killer (NK) cells participate in local control of tumor growth in CTCL skin. Immunohistochemistry and flow cytometry analysis of the density, localization, phenotype and function of NK cells in twenty-nine fresh or formalin-fixed skin biopsies from twenty-four CTCL patients and twenty-three biopsies from twenty healthy controls highlighted higher numbers of CD56 + CD3 - NK cells in CTCL skin. A reduced fraction of CTCL skin NK cells expressed the maturation marker CD57, the cytotoxic protein granzyme B and the activation marker CD69, indicating reduced tumor-killing abilities of the NK cells. Retained expression of immune checkpoint proteins or inhibitory proteins including PD1, TIM3, LAG3, CD73 and NKG2A and the activating receptors CD16 and NKp46 indicated maintained effector functions. Indeed, the capacity of NK cells to produce anti-tumor acting IFNγ upon PMA+ionomycin stimulation was similar in cells from CTCL and healthy skin. Co-cultures of primary human NK cells or the NK cell line NKL with CTCL cells resulted in reduced levels of granzyme B and CD69, indicating that close cellular interactions with CTCL cells induced the impaired functional NK cell phenotype. In conclusion, increased numbers of NK cells in CTCL skin exhibit a partially impaired phenotype in terms of activity. Enhancing NK cell activity with NK cell activating cytokines such as IL-15 or immune checkpoint blockade therefore represents a potential immunotherapeutic approach in CTCL., Competing Interests: HB has received honoraria from participating in advisory boards of Kyowa Kirin in 2019 and 2022. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Scheffschick, Nenonen, Xiang, Winther, Ehrström, Wahren-Herlenius, Eidsmo and Brauner.)

Primary cutaneous lymphoma is a heterogeneous group of diseases where the malignant lymphocytes are primarily present in the skin at the time of diagnosis. The most common type of primary cutaneous lymphoma is mycosis fungoides. Early stages of mycosis fungoides present with flat or slightly elevated red skin lesions and can resemble eczema or psoriasis. In advanced stages erythrodermia or skin tumors can develop. For many patients with mycosis fungoides effective albeit not curative treatment is available. Large randomized treatment studies for mycosis fungoides are largely lacking, which makes decisions on treatment strategy difficult. The new national clinical guidelines will hopefully enable more equal care for patients with mycosis fungoides and other types of primary cutaneous lymphoma in Sweden.