Epigenetic Priming by Hypomethylation Enhances the Immunogenic Potential of Tolinapant in T-cell Lymphoma

• DOI: 10.1158/2767-9764.crc-23-0415
• Publication Date: 2024-05-10T12:57:16Z
• Authors: George A. Ward; Zhiqiang Zhang; Simone Jueliger; Ilya S. Potapov; Matthew P. Davis; Adam R. Boxall; Jason Taylor; Harold Keer; Andrea Biondo; John F. Lyons; Martin Sims; Tomoko Smyth
• Keywords: Priming (agriculture)

Abstract Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion resistance to apoptosis significant factors in tumorigenesis drug resistance. Bypassing apoptotic pathways eliciting another form regulated death, namely necroptosis, an immunogenic (ICD), may override Here, we present mechanistic rationale combining tolinapant, antagonist inhibitor proteins (IAP), with decitabine, a hypomethylating agent (HMA), T-cell lymphoma (TCL). Tolinapant treatment alone TCL cells vitro syngeneic vivo models demonstrated that ICD markers can be upregulated, have shown epigenetic priming decitabine further enhances this effect. The clinical relevance was confirmed by direct measurement plasma from patients peripheral treated tolinapant. We showed increased levels necroptosis lines, along expression cancer-specific antigens (such as cancer testis antigens) increases genes involved IFN signaling induced HMA treatment, together deliver strong adaptive immune response tumor. These results highlight potential tolinapant combination could lead evaluation. Significance: IAP induce key immune-activating event, TCL. Combination DNA hypomethylation sensitivity primes resistant re-expressing necrosome proteins. In addition, leads neoantigen expression, providing molecular novel therapeutic option.