B-T.28: Multi-modal profiling uncovers a MYC-MIZ1-lysosomal axis controlling immune exclusion in pancreatic cancer
MYC deregulation in PDAC has been shown to drive tumorigenesis and immune evasion by limiting tumor antigen expression, reducing T cell infiltration, and maintaining an immunosuppressive tumor microenvironment (TME). However, the mechanisms by which MYC orchestrates immune evasion remain incompletely understood.
To address this, we combined bulk, single-cell, and spatial transcriptomics with metabolomics to characterize tumor-immune interactions in an orthotopic KPC model of pancreatic cancer. Analysis across these modalities revealed that MYC-mediated immune evasion does not merely depend on suppression of antigen presentation. Instead, MYC depletion restores amino acid availability in the TME. This is associated with increased expression of amino acid-responsive gene programs across multiple immune cell populations.
Mechanistically, chromatin binding and transcriptomic analysis identifies MYC/MIZ1 driven repression of lysosomal genes as a key mediator of this phenotype. MYC increases tumor reliance on extracellular amino acids by limiting lysosomal protein turnover. Consistently, MYC variants that fail to repress lysosomal genes maintain proliferation in vitro, but do not support immune evasion or sustained tumor growth in vivo.
Finally, by selectively and acutely inhibiting transport of soluble amino acids into tumors, we restore amino acid availability in the TME, enhance immune activity, and induce rapid, CD4+ T cell-mediated tumor clearance, resulting in long-term survival.
Together, these results demonstrate how integrative analysis of multi-modal datasets can uncover functional couplings between tumor-intrinsic transcriptional programs and immune cell metabolic states. This framework links MYC/MIZ1-dependent regulation to ecosystem-level metabolic constraints and suggests that disrupting these regulatory interactions may reverse immune suppression in PDAC.
Co-authors: Bastian Krenz, Greta Mattavelli, Martin Eilers
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