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

Academic Article

Abstract

  • 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 ACOSOG Z1031 (Alliance) neoadjuvant aromatase inhibitor (AI) trial identified upregulated genes in Luminal (Lum) B breast cancers that correlated with AI-resistant tumor proliferation (percentage of Ki67-positive cancer nuclei, Pearson r > 0.4) (33 cases Ki67 > 10% on AI) vs LumB breast cancers that were more AI sensitive (33 cases Ki67 < 10% on AI). Overrepresentation analysis was performed using WebGestalt. All statistical tests were two-sided. RESULTS: Thirty candidate genes positively correlated (r ≥ 0.4) with AI-resistant proliferation in LumB and were upregulated greater than twofold. Gene ontologies identified that the targetable immune checkpoint (IC) components IDO1, LAG3, and PD1 were overrepresented resistance candidates (P ≤ .001). High IDO1 mRNA was associated with poor prognosis in LumB disease (Molecular Taxonomy of Breast Cancer International Consortium, hazard ratio = 1.43, 95% confidence interval = 1.04 to 1.98, P = .03). IDO1 also statistically significantly correlated with STAT1 at protein level in LumB disease (Pearson r = 0.74). As a composite immune tolerance signature, expression of IFN-γ/STAT1 pathway components was associated with higher baseline Ki67, lower estrogen, and progesterone receptor mRNA levels and worse disease-specific survival (P = .002). In a tissue microarray analysis, IDO1 was observed in stromal cells and tumor-associated macrophages, with a higher incidence in LumB cases. Furthermore, IDO1 expression was associated with a macrophage mRNA signature (M1 by CIBERSORT Pearson r = 0.62 ) and by tissue microarray analysis. CONCLUSIONS: Targetable IC components are upregulated in the majority of endocrine therapy-resistant LumB cases. Our findings provide rationale for IC inhibition in poor-outcome ER-positive breast cancer.

    • Authors

    Keywords

  • Antigens, CD, Antineoplastic Agents, Hormonal, Aromatase Inhibitors, Breast Neoplasms, Cell Proliferation, Drug Resistance, Neoplasm, Female, Humans, Immune Tolerance, Indoleamine-Pyrrole 2,3,-Dioxygenase, Interferon-gamma, Letrozole, Prognosis, Programmed Cell Death 1 Receptor, STAT1 Transcription Factor, Signal Transduction, Tissue Array Analysis, Transcriptome, Up-Regulation, Lymphocyte Activation Gene 3 Protein

    • Digital Object Identifier (doi)

    Author List

  • Anurag M; Zhu M; Huang C; Vasaikar S; Wang J; Hoog J; Burugu S; Gao D; Suman V; Zhang XH

    • Start Page

  • 737

    • End Page

  • 746

    • Volume

  • 112

    • Issue

  • 7