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Dupilumab inhibits proliferation of malignant lymphocytes in Sezary syndrome and boosts anti-tumor immunity

ABSTRACT: Patients with Sezary syndrome (SS), the aggressive leukemic variant of cutaneous T-cell lymphoma, have few therapeutic options and a poor prognosis. We previously showed that the IL4/IL13 signaling pathway is critical in SS tumorigenesis. Here we investigated the potential therapeutic effect of inhibiting IL4/IL13 signaling with REGN668 (Dupilumab), a monoclonal antibody that blocks the IL4/IL13 pathway by targeting IL4Rα, the common subunit of the IL4 and IL13 receptors. Using recent advances in single-cell RNA sequencing we defined transcriptional changes and molecular mechanisms associated with REGN668 treatment in malignant and reactive T lymphocytes as well as in monocytes and dendritic cells from the peripheral blood of SS patients. We observed variable responses across patient samples and downregulation of patient-specific pathways in malignant and reactive immune cells. Significantly, we found that REGN668 downregulates expression of common pro-tumorigenic processes in malignant lymphocytes, including cell division, DNA damage/repair, autophagy, and various pathways associated with T-cell signaling. A key finding from functional ex vivo studies was that REGN668 inhibits proliferation of malignant lymphocytes more efficiently than blocking either IL4 or IL13 signaling alone. Furthermore, we found that Dupilumab also reverts the immunosuppressive phenotype of non-clonal T lymphocytes and myeloid cells in the SS tumor microenvironment, including the function of MDSCs as well as Th2 and exhaustion pathways. Although some case reports have cast doubt on the efficacy of Dupilumab in treating SS patients, our results suggest that the effects of Dupilumab are pathway-specific and that it may be a critical component of a multi-pathway treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290850 | GEO | 2025/10/06

REPOSITORIES: GEO

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Project description:Background. Sézary syndrome (SS) is an aggressive and leukemic variant of Cutaneous T-cell Lymphoma (CTCL) with an incidence of 1-case per million people per year. It is characterized by a complex and heterogeneous profile of genetic alterations that has so far precluded the development of a specific and definitive therapeutic intervention.Methods. Deep-RNA-sequencing (RNA-seq) data were used to analyze the single nucleotide variants (SNVs) carried by 128 putative CTCL-driver genes, previously identified as mutated in genomic studies, in longitudinal SS samples collected from 17 patients subjected to extracorporeal photopheresis (ECP) with Interferon-α. Results obtained were integrated with Whole Exome Sequencing (WES) data. SNVs were validated using the Sanger method. Pathway analysis was performed with g:Profiler web server (https://biit.cs.ut.ee/gprofiler/gost). Statistical analyses were performed with GraphPad PRISM 8 software.Results.Nonsynonymous SNVs were identified in 56 genes. Integration of RNA-seq with WES data revealed that about half of these genes contained somatic mutations. Among them, the most frequently transcribed mutated genes were TET2, JAK3, NCOR1, PDCD11, RHOA, and TP53.Nearly all the remaining genes had germline-restricted mutations, and included ARID1A, ATM, ATR, CREBBP, POLD1, and POT1 genes, which are involved in DNA repair, homologous recombination, and chromatin remodeling, and the CROCC gene, implicated in centrosome cohesion. Monitoring of the mutated genes, identified within an enlarged panel of CTCL associated genes, revealed their reduction in almost 70% of SS patients as well as a significant decline of total number of mutations (SNVs) during ECP treatment. Several mutated genes persisted post-therapy, representing novel candidates associated with ECP resistance that could also have a potential prognostic relevance.Notably, these genes mainly converge on pathways related to DNA repair (ATR, ATRIP, POLD1, TP53, TP53BP1/2) which might represent novel targets to be explored in combination with ECP.Conclusions. This is the first evaluation in SS of expressed mutations in a large panel of CTCL-driver genes. Also innovative is the monitoring of mutated genes in patients' malignant lymphocytes during ECP, a first-line treatment of In review CTCL, which highlights novel candidates associated with ECP resistance that might unmask novel pharmacological vulnerabilities to be exploited during ECP for a personalized treatment

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Dupilumab inhibits proliferation of malignant lymphocytes in Sezary syndrome and boosts anti-tumor immunity

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