The role of drug-induced immunopeptidome alterations for the elimination of residual disease in acute myeloid leukemia

• Applicant: Dr. Annika Stephanie Nelde
• Subject Area: Hematology, Oncology ; Immunology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565858756

Anti-cancer T cell responses play a major role in the immune control of residual disease in acute myeloid leukemia (AML). Effective immune control requires functional tumor-specific T cells as well as robustly presented antigen targets, namely tumor-associated HLA-presented peptides, on the tumor cells. Whereas several anti-cancer drugs have been developed to improve anti-cancer T cells (e.g. immune checkpoint inhibitors), little is known how cancer drugs affect tumor antigen presentation. In recent years, novel tumor antigens were characterized based on the mass spectrometry-based identification of the entirety of naturally presented HLA ligands, termed the immunopeptidome. Furthermore, it was shown that the mode of action of a specific drug is directly mirrored in the immunopeptidome resulting in treatment-associated HLA ligands, which may represent promising targets for the development of combinatorial immunotherapy approaches to eliminate residual post-therapy tumor cells. In this project, the applicant will elucidate the effect of DNA methyltransferase (DNMT) inhibitors, so-called hypomethylating agents, on the immunopeptidome of AML. For these substances an immune-modulatory activity was suggested based on the induction of silenced genes and increase of genomic instability. The applicant aims to establish novel therapies combining these drugs with immunotherapeutic approaches targeting specific drug-induced antigens to eradicate residual AML cells. To achieve this goal, the applicant will evaluate drug-induced immunopeptidome alterations of post-therapeutic residual AML cells. To mechanistically link the drug-induced alterations with the drug mode of action immunopeptidome data will be combined mRNA sequencing data. This multi-omics analyses will enable the characterization of drug-induced antigen targets including treatment-induced non-mutated peptides, cryptic peptides derived from non-canonical transcripts and neoepitopes. These antigens will then be evaluated for their ability to induced anti-cancer T cell responses and thus for their impact on T cell-based immune control in AML patients treated with the respective drugs. Finally, combinatorial therapy approaches will be evaluated in vivo using treatment-associated peptide vaccines to eliminate residual leukemia cells after drug treatment in a syngenic mouse model. This project will not only shed light on the mechanism of cancer drug-induced immune control but also will provide a rational for the clinical evaluation of combinatorial drug-induced peptide-based immunotherapies to eradicated post therapeutic residual leukemic cells in AML patients.

• DFG Programme: Research Grants