Beyond CD30 Targeting: Brentuximab Vedotin Triggers Immunogenic Cell Death and Antitumor Immunity in Mycosis Fungoides, Overcoming Resistance via BCL2 Inhibition

Background: Mycosis fungoides (MF), the most common subtype of cutaneous T cell lymphoma (CTCL), has poor prognosis in advanced stages due to lack of effective therapies. Brentuximab vedotin (BV), an antigen-drug conjugate targeting CD30, is approved for CD30+ MF after prior systemic treatment. However, many patients develop resistance with unclarified mechanisms. Method: We conducted single-cell RNA sequencing on 13 paired tumor samples from 6 CD30+ MF patients treated with BV. Eight post-treatment samples were grouped into responsive (n = 5) and non-responsive (n = 3) lesions based on pathologic response. Combination effects of BV and BCL2 inhibitors were assessed in CD30+ CTCL cell lines. Result: BV induced immunogenic cell death (ICD) in both CD30+ and CD30- malignant T cells, enhancing their MHC-II-mediated antigen presentation in responsive lesions. Besides, BV specifically enhanced the IFNα/γ responses in CD30- malignant T cells. These coincided with TME reprogramming: diminished immunosuppressive function of Tregs and activated antitumor immunity mediated by dendritic cells, CD8+ T and NK cells. In non-responsive lesions, resistance was driven by distinct mechanisms: CD30+ malignant T cells upregulated the drug efflux transporter ABCB1 and exhibited impaired endosomal processing, while CD30- tumor cells overexpressed the anti-apoptotic protein BCL2 and displayed blunted IFN response. We confirmed potent synergy between BV and BCL2 inhibitors in CTCL cell lines, overcoming resistance. Conclusion: Beyond direct CD30+ targeting, BV transforms the immunosuppressive milieu by inducing ICD in tumor cells and suppressing Tregs. Resistance involves ABCB1 upregulation in CD30+ cells and BCL2-mediated survival in CD30- cells. Combining BV with BCL2 inhibitors represents a promising strategy to overcome resistance in CD30+ CTCL.