CD30 as a therapeutic target in cutaneous T-cell lymphoma

Cutaneous T-cell lymphomas (CTCLs) are a rare group of non-Hodgkin lymphomas (NHL) primarily affecting the skin. The most common subtypes comprise Mycosis fungoides (MF), Sézary syndrome (SS), and CD30+ lymphoproliferative disorders (LPD). Treatment of CTCL is challenging as therapeutic options are limited. Especially, advanced MF and SS exhibit impaired prognosis. However, treatment of CD30-positive CTCL with Brentuximab vedotin (BV) achieves profound effects. BV is an antibody-drug conjugate (ADC), consisting of a monoclonal anti-CD30 antibody conjugated with the cytotoxic agent monomethyl auristatin E (MMAE). Surprisingly, a recent meta-analysis of five clinical trials demonstrated that CD30 expression, analyzed by immunohistochemistry, did not predict the clinical response to BV. Therefore, we investigated in vitro the relationship between CD30 expression and BV sensitivity. Established CTCL cell lines originated from different CTCL subtypes were genetically modified regarding their CD30 expression status by either CRISPR/Cas9-mediated CD30 knockout (KO) or inducible ectopic CD30 expression by means of a Tet-On system. In addition, ex vivo experiments were performed using primary tumor cells of patients with Sézary syndrome. In contrast to the clinical observations, our data revealed a clear relation between CD30 expression levels and BV sensitivity. As acquired resistance to BV is a common feature in CTCL, we next focused on potential resistance mechanisms under BV selection. To this end, BV-tolerant CTCL cell lines were generated by constant exposure to BV. Indeed, we observed downregulation in CD30, upregulation of CD30L expression as well as decreased MMAE sensitivity, suggesting all three as potential modes of resistance. Given the crucial role of CD30 in the treatment of CTCL with BV, we then examined which signaling pathways are involved in CD30 expression. Our data demonstrate complex regulation of CD30 by diverse signaling pathways. While the JAK/STAT signaling pathway is essential for basal CD30 expression in CTCL cell lines with oncogenic Janus kinase fusion (JAK) proteins, other signaling pathways such as the PI3K/AKT pathway contribute to basal CD30 expression in CTCL cell lines. Moreover, both JAK/STAT and PI3K/AKT pathways support activation-induced CD30 expression. These findings help to better understand the role of CD30 in CTCL from which the treatment with BV may benefit in the future.