Immune Checkpoint Profiles in Luminal B Breast Cancer (Alliance)

J Natl Cancer Inst. 2020 Jul 1;112(7):737-746. doi: 10.1093/jnci/djz213.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Antigens, CD
  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
  • IDO1 protein, human
  • IFNG protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Letrozole
  • Interferon-gamma
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, human