Immune Checkpoint Profiles in Luminal B Breast Cancer (Alliance).

BACKGROUND: Unlike estrogen receptor (ER) negative breast cancer, ER-positive breast cancer outcome is less influenced by lymphocyte content indicating the presence of immune tolerance mechanisms that may be specific to this disease subset. METHODS: A supervised analysis of microarray data from the Alliance/ACOSOG Z1031 neoadjuvant aromatase inhibitor (AI) trial identified upregulated genes in Luminal B breast cancers that correlated with AI-resistant tumor proliferation (Pearson's correlation r ≥ 0.4 with Ki67) (33 cases Ki67 >10% on AI) versus Luminal-B breast cancers that were more AI-sensitive (33 cases Ki67 2 fold. Gene ontologies identified that the targetable immune-checkpoint components IDO1, LAG3, and PD1 were over-represented resistance candidates (p ≤ 0.001). High IDO1 mRNA associated with poor prognosis in luminal-B disease (METABRIC, HR = 1.43, CI 1.04 - 1.98, p = 0.03). IDO1 also statistically significantly correlated with STAT1 at protein level in luminal-B disease (Pearson's r = 0.74). As a composite immune tolerance signature, expression of IFN-γ/STAT1 pathway components associated with higher baseline Ki67, lower estrogen and progesterone receptor mRNA levels and worse disease specific survival (p = 0.002). In a tissue microarray analysis (TMA), IDO1 was observed in stromal cells and tumor-associated macrophages, with a higher incidence in Luminal-B cases. Furthermore, IDO1 expression associated with a macrophage mRNA signature (M1 by CIBERSORT Pearson's r = 0.62 ) and also by TMA analysis. CONCLUSION: Targetable immune-checkpoint components are upregulated in majority of endocrine therapy resistant Luminal-B cases. Our findings provide rationale for immune checkpoint inhibition in poor outcome ER+ breast cancer.