% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Wang:282366,
      author       = {L. Wang and R. Luo$^*$ and K. Onyshchenko$^*$ and X.
                      Rao$^*$ and M. Wang and B. Menz and S. Gaedicke and A.-L.
                      Grosu$^*$ and E. Firat and G. Niedermann$^*$},
      title        = {{A}dding liposomal doxorubicin enhances the abscopal effect
                      induced by radiation/α{PD}1 therapy depending on tumor cell
                      mitochondrial {DNA} and c{GAS}/{STING}.},
      journal      = {Journal for ImmunoTherapy of Cancer},
      volume       = {11},
      number       = {8},
      issn         = {2051-1426},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2023-01748},
      pages        = {e006235},
      year         = {2023},
      abstract     = {Localized radiotherapy (RT) can cause a T cell-mediated
                      abscopal effect on non-irradiated tumor lesions, especially
                      in combination with immune checkpoint blockade. However,
                      this effect is still clinically rare and improvements are
                      highly desirable. We investigated whether triple combination
                      with a low dose of clinically approved liposomal doxorubicin
                      (Doxil) could augment abscopal responses compared with
                      RT/αPD-1 and Doxil/αPD-1. We also investigated whether the
                      enhanced abscopal responses depended on the mitochondrial
                      DNA (mtDNA)/cyclic GMP-AMP synthase (cGAS)/stimulator of
                      interferon genes (STING)/IFN-I pathway.We used Doxil in
                      combination with RT and αPD-1 in two tumor models
                      (B16-CD133 melanoma and MC38 colon carcinoma) with mice
                      bearing two tumors, only one of which was irradiated.
                      Mechanistic studies on the role of the
                      mtDNA/cGAS/STING/IFN-I axis were performed using inhibitors
                      and knockout cells in vitro as well as in mice.Addition of a
                      single low dose of Doxil to RT and αPD-1 strongly enhanced
                      the RT/αPD-1-induced abscopal effect in both models.
                      Complete cures of non-irradiated tumors were mainly observed
                      in triple-treated mice. Triple therapy induced more
                      cross-presenting dendritic cells (DCs) and more
                      tumor-specific CD8+ T cells than RT/αPD-1 and Doxil/αPD-1,
                      particularly in non-irradiated tumors. Coincubation of
                      Doxil-treated and/or RT-treated tumor cells with DCs
                      enhanced DC antigen cross-presentation which is crucial for
                      inducing CD8+ T cells. CD8+ T cell depletion or implantation
                      of cGAS-deficient or STING-deficient tumor cells abolished
                      the abscopal effect. Doxorubicin-induced/Doxil-induced
                      IFNβ1 markedly depended on the cGAS/STING pathway.
                      Doxorubicin-treated/Doxil-treated tumor cells depleted of
                      mtDNA secreted less IFNβ1, of the related T cell-recruiting
                      chemokine CXCL10, and ATP; coincubation with mtDNA-depleted
                      tumor cells strongly reduced IFNβ1 secretion by DCs.
                      Implantation of mtDNA-depleted tumor cells, particularly at
                      the non-irradiated/abscopal site, substantially diminished
                      the Doxil-enhanced abscopal effect and tumor infiltration by
                      tumor-specific CD8+ T cells.These data show that single
                      low-dose Doxil can substantially enhance the
                      RT/αPD-1-induced abscopal effect, with a strong increase in
                      cross-presenting DCs and CD8+ tumor-specific T cells
                      particularly in abscopal tumors compared with RT/αPD-1 and
                      Doxil/αPD-1. Moreover, they indicate that the
                      mtDNA/cGAS/STING/IFN-I axis is important for the
                      immunogenic/immunomodulatory doxorubicin effects. Our
                      findings may be helpful for the planning of clinical
                      radiochemoimmunotherapy trials in (oligo)metastatic
                      patients.},
      keywords     = {Combined Modality Therapy (Other) / Immunotherapy (Other) /
                      Programmed Cell Death 1 Receptor (Other) /
                      Radioimmunotherapy (Other) / Radiotherapy (Other)},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37640480},
      doi          = {10.1136/jitc-2022-006235},
      url          = {https://inrepo02.dkfz.de/record/282366},
}