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@ARTICLE{Soliman:302852,
      author       = {N. Soliman and T. Nedelko and G. Mandracci and S. Enssle
                      and V. Grass and J. C. Fischer and F. Bassermann$^*$ and H.
                      Poeck and S. Kobold$^*$ and N. El Khawanky and S. Heidegger},
      title        = {{T}argeting {I}ntracellular {I}nnate {RNA}-{S}ensing
                      {S}ystems {O}vercomes {R}esistance to {CAR} {T}-cell
                      {T}herapy in {S}olid {T}umors.},
      journal      = {Cancer research},
      volume       = {85},
      number       = {14},
      issn         = {0099-7013},
      address      = {Philadelphia, Pa.},
      publisher    = {AACR},
      reportid     = {DKFZ-2025-01392},
      pages        = {2679 - 2693},
      year         = {2025},
      abstract     = {Despite the remarkable success of chimeric antigen receptor
                      (CAR) T cells in certain hematologic malignancies, only
                      modest responses have been achieved in solid tumors.
                      Defective cell death pathways have recently been suggested
                      as a tumor-intrinsic form of resistance to CAR T-cell
                      treatment. In this study, we showed that insufficient
                      activity of the innate RNA-sensing receptor system retinoic
                      acid-inducible gene I (RIG-I)/mitochondrial antiviral
                      signaling protein (MAVS) leads to tumor cell-inherent
                      resistance to CAR T-cell attack. Active RIG-I/MAVS signaling
                      in tumor cells primed intrinsic mitochondrial apoptosis
                      pathways and expression of cell death receptors, which
                      funneled into CAR T-cell-triggered cell death. CAR T-cell
                      reliance on tumor-intrinsic RIG-I signaling was observed in
                      various murine and human cancer types, independent of the
                      CAR construct used, and the dependence was most pronounced
                      under conditions with low target antigen expression or low
                      effector/target ratios. RIG-I-induced proapoptotic priming
                      of CAR T-cell susceptibility involved auto-/paracrine type-I
                      IFN signaling loops and could spread to bystander tumor
                      cells. Strong tumor-intrinsic RIG-I/MAVS signaling imprinted
                      an activated cytolytic phenotype on tumor-interacting CAR T
                      cells. Agonist-mediated targeting of the RIG-I pathway in
                      the tumor microenvironment rendered murine melanoma
                      susceptible to CAR T-cell therapy in vivo with enhanced
                      infiltration of active CAR T cells. Together, these data
                      identify insufficient RIG-I/MAVS activity and associated
                      impaired cell death signaling in malignant cells as a
                      resistance mechanism to CAR T cells. Targeting
                      tumor-intrinsic RIG-I is a potential strategy to sensitize
                      solid tumors to CAR T-cell treatment.Insufficient activity
                      of the RIG-I/MAVS pathway is a tumor intrinsic resistance
                      mechanism to CAR T cells, providing the rationale for
                      targeting RIG-I to optimize CAR T efficacy in patients with
                      solid cancers.},
      keywords     = {Animals / Humans / Mice / Immunotherapy, Adoptive: methods
                      / Receptors, Chimeric Antigen: immunology / Receptors,
                      Chimeric Antigen: metabolism / DEAD Box Protein 58:
                      metabolism / DEAD Box Protein 58: immunology / Signal
                      Transduction / Neoplasms: therapy / Neoplasms: immunology /
                      Neoplasms: pathology / Adaptor Proteins, Signal Transducing:
                      metabolism / Adaptor Proteins, Signal Transducing:
                      immunology / Apoptosis / Immunity, Innate / Cell Line, Tumor
                      / Tumor Microenvironment / Receptors, Immunologic /
                      Receptors, Chimeric Antigen (NLM Chemicals) / DEAD Box
                      Protein 58 (NLM Chemicals) / RIGI protein, human (NLM
                      Chemicals) / Adaptor Proteins, Signal Transducing (NLM
                      Chemicals) / MAVS protein, human (NLM Chemicals) /
                      Receptors, Immunologic (NLM Chemicals)},
      cin          = {MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40305099},
      pmc          = {pmc:PMC12260516},
      doi          = {10.1158/0008-5472.CAN-24-3425},
      url          = {https://inrepo02.dkfz.de/record/302852},
}