Research Assistant Karmanos Cancer Inst., Wayne State Univ. Detroit, Michigan, United States
Disclosure(s):
Savannah Hughes: No financial relationships to disclose
Introduction/Rationale: Trastuzumab, an anti-HER2 targeted immunotherapy (ITx), has changed the landscape of HER2+ breast cancer survival, but drug resistance and disease recurrence still present a problem. Patients who develop anti-tumor immunity after targeted ITx show improved long-term benefit, but host-intrinsic mechanisms regulating immune priming remain unclear.
Methods: (Diversity OutbredxBALB/c)F1 (DOF1) mice bearing HER2/neu+ TUBO mammary tumors were treated with anti-HER2/neu mAb 7.16.4. Genetic linkage analysis was performed in R/qtl2 to identify loci associated with response and select Collaborative Cross (CC) mouse models with driver genetics. scRNAseq was performed on CD45+ TUBO infiltrates from CCF1 mice. To measure cross-presentation, DC2.4 dendritic cells were transduced with shSNX3 or control lentiviruses and cocultured with TUBO cells expressing ovalbumin (OVA) prior to the addition of OVA-specific OT-I CD8 T cells. scRNAseq was performed on 46 trastuzumab-treated HER2+ breast cancer samples (~60% responders) collected prior to therapy.
Results: We find that host genetic background influences endogenous immune priming after targeted ITx in mice. DOF1 TUBO-bearing mice exhibited differential response to 7.16.4 treatment; ~45% of mice eliminated primary tumor with protection against contralateral rechallenge. Genetic linkage analysis and tumor immune infiltrate scRNAseq identified SNX3 as a potential regulator of response to targeted ITx. We observed increased OT-I activation in the presence of DC2.4/shSNX3, suggesting SNX3 negatively regulates antigen cross-presentation. Supporting this hypothesis, our human breast cancer scRNAseq dataset showed an inverse correlation of trastuzumab response with dendritic cell SNX3 expression.
Conclusion: We demonstrate that genetic background influences response to targeted ITx and identify SNX3 as a regulator of response through antigen presentation to CD8 T cells. Future studies aim to leverage SNX3 as a novel actionable gene to improve targeted ITx outcomes.
