Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma

• Published in: Communications biology 2023-12, Vol.6 (1), p.1299-1299, Article 1299
• Main Authors: Munawar, Umair, Zhou, Xiang, Prommersberger, Sabrina, Nerreter, Silvia, Vogt, Cornelia, Steinhardt, Maximilian J., Truger, Marietta, Mersi, Julia, Teufel, Eva, Han, Seungbin, Haertle, Larissa, Banholzer, Nicole, Eiring, Patrick, Danhof, Sophia, Navarro-Aguadero, Miguel Angel, Fernandez-Martin, Adrian, Ortiz-Ruiz, Alejandra, Barrio, Santiago, Gallardo, Miguel, Valeri, Antonio, Castellano, Eva, Raab, Peter, Rudert, Maximilian, Haferlach, Claudia, Sauer, Markus, Hudecek, Michael, Martinez-Lopez, J., Waldschmidt, Johannes, Einsele, Hermann, Rasche, Leo, Kortüm, K. Martin
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/2; 13/21; 14; 38; 38/39; 38/91; 42; 45; 631/250/251; 692/308/575; 96/2; Acute lymphoblastic leukemia; Antibodies, Monoclonal - therapeutic use; Biomedical and Life Sciences; Cancer therapies; Cross-resistance; Death; FADD protein; Fas-Associated Death Domain Protein; Genotoxicity; Humans; Immunoconjugates; Immunotherapy; Immunotherapy - methods; Life Sciences; Lymphatic leukemia; Lymphocytes T; Monoclonal antibodies; Multiple myeloma; Multiple Myeloma - drug therapy; Patients; Receptors, Death Domain; T-Lymphocytes
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-05683-4

The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM. Defect in the death receptor signally caused by impaired FADD/BID expression leads to failure of T-cell mediated immunotherapy in multiple myeloma patients.