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Genetically engineered ErbB2 overexpression sensitizes organoid-derived tumors to checkpoint inhibition in a syngeneic model of gastric cancer

ABSTRACT: ERBB2/HER2 is overexpressed in ~15% of gastric cancers due to amplification or mutation of the ERBB2 locus. While the tumor cell-intrinsic consequences of ERBB2 overexpression are well understood, much less is known about its effects on the tumor microenvironment. Here, we have developed genetically engineered ectopic and orthotopic syngeneic models of organoid-based gastric cancer that have allowed us to study the tumor microenvironment of ErbB2-overexpressing tumors. We find that ErbB2 drives the infiltration of CD4+ and CD8+ T-cells, which express granzymes, FasL and surface markers indicating chronic activation, and in the case of CD8+ T-cells, have undergone clonal expansion. The adoptive transfer of T-cells sorted from ErbB2-overexpressing tumors reduces the growth of ErbB2-expressing, but not control tumors in T-cell-deficient recipients. PD1-specific checkpoint blockade synergizes with an ErbB2-targeting antibody to reduce the growth of ErbB2-expressing, but not control tumors. Mechanistically, ErbB2 overexpression results in micronuclei formation and the transcriptional activation of numerous interferon-responsive genes in vitro and in vivo; mice lacking the type I interferon receptor show higher engraftment rates and lower T-cell infiltration than wildtype controls. The combined data indicate that ErbB2, perhaps by driving micronuclei formation, has immunogenic properties that manifest in the form of increased T-cell infiltration and expansion, and can be exploited therapeutically by combining PD1-directed checkpoint blockade with ErbB2-targeted therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE300738 | GEO | 2026/02/25

REPOSITORIES: GEO

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