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

Abstract

BACKGROUND: ERBB2/HER2 is overexpressed or mutated in ~15% of gastric cancers due to amplification or mutation of thelocus. While the tumor cell-intrinsic consequences of ERBB2 overexpression are well understood, much less is known about its effects on the tumor microenvironment. METHODS: 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, using spectral flow cytometry, single cell RNA sequencing, and TCR repertoire sequencing. Interventions such as anti-Erbb2 and anti-PD1 antibody treatments were used as well. RESULTS: We find that ErbB2 drives the infiltration of CD4and CD8T-cells, which express granzymes, FasL, and surface markers indicating chronic activation, and in the case of CD8T-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. PD-1-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 wild-type controls. CONCLUSIONS: 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, which can be exploited therapeutically by combining PD1-directed checkpoint blockade with ErbB2-targeted therapy.