Co-expression of CD30 and SLFN11 serves as a dual biomarker for the treatment of cutaneous T-cell lymphoma

Advanced-stage cutaneous T-cell lymphoma (CTCL) is treated with diverse modalities, including DNA-damaging agents, anti-CD30 antibody–drug conjugates, and histone deacetylase (HDAC) inhibitors. Schlafen 11 (SLFN11) has emerged as a key determinant of sensitivity to DNA-damaging agents, yet its role in CTCL remains unclear. Here, we examined SLFN11 expression in two major CTCL subtypes—mycosis fungoides (MF) and Sézary syndrome (SS). Immunohistochemistry revealed SLFN11 positivity in 52% of MF (13/25) and 80% of SS (4/5) cases, with multivariate analysis showing a significant correlation between SLFN11 and CD30 expression. In normal human peripheral blood mononuclear cells, CD3/CD28/IL-2 stimulation induced co-expression of SLFN11 and CD30 in T cells, which was accompanied by heightened sensitivity to DNA-damaging agents. The JAK inhibitor cerdulatinib suppressed both markers. Among five CTCL cell lines, HUT78—expressing the highest SLFN11 levels—was the most sensitive to DNA-damaging agents, whereas SLFN11 knockout conferred resistance. Attempts to restore SLFN11 expression in SLFN11-low CTCL cells using six (pre)clinical HDAC inhibitors produced inconsistent results across cell lines and drugs. Together, these findings identify SLFN11 and CD30 as co-expressed therapeutic targets in CTCL and support the rationale for CD30-directed antibody–DNA-damaging agent conjugates as a precision treatment strategy.