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@ARTICLE{Vornholz:274320,
author = {L. Vornholz and S. E. Isay and Z. Kurgyis and D. C. Strobl
and P. Loll and M. H. Mosa and M. D. Luecken and M. Sterr
and H. Lickert and C. Winter$^*$ and F. R. Greten$^*$ and H.
Farin$^*$ and F. J. Theis and J. Ruland$^*$},
title = {{S}ynthetic enforcement of {STING} signaling in cancer
cells appropriates the immune microenvironment for
checkpoint inhibitor therapy.},
journal = {Science advances},
volume = {9},
number = {11},
issn = {2375-2548},
address = {Washington, DC [u.a.]},
publisher = {Assoc.},
reportid = {DKFZ-2023-00534},
pages = {eadd8564},
year = {2023},
abstract = {Immune checkpoint inhibitors (ICIs) enhance anticancer
immunity by releasing repressive signals into tumor
microenvironments (TMEs). To be effective, ICIs require
preexisting immunologically 'hot' niches for tumor antigen
presentation and lymphocyte recruitment. How the mutational
landscape of cancer cells shapes these immunological niches
remains poorly defined. We found in human and murine
colorectal cancer (CRC) models that the superior antitumor
immune response of mismatch repair (MMR)-deficient CRC
required tumor cell-intrinsic activation of cGAS-STING
signaling triggered by genomic instability. Subsequently, we
synthetically enforced STING signaling in CRC cells with
intact MMR signaling using constitutively active STING
variants. Even in MMR-proficient CRC, genetically encoded
gain-of-function STING was sufficient to induce cancer
cell-intrinsic interferon signaling, local activation of
antigen-presenting cells, recruitment of effector
lymphocytes, and sensitization of previously 'cold' TMEs to
ICI therapy in vivo. Thus, our results introduce a rational
strategy for modulating cancer cell-intrinsic programs via
engineered STING enforcement to sensitize resistant tumors
to ICI responsiveness.},
cin = {MU01 / FM01},
ddc = {500},
cid = {I:(DE-He78)MU01-20160331 / I:(DE-He78)FM01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:36921054},
doi = {10.1126/sciadv.add8564},
url = {https://inrepo02.dkfz.de/record/274320},
}