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J Natl Cancer Inst. 2019 Oct 30. pii: djz213. doi: 10.1093/jnci/djz213. [Epub ahead of print]

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

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Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
Department of Medicine, Baylor College of Medicine, Houston, Texas.
Genetic Pathology Evaluation Centre; University of British Columbia, Vancouver.
Pathology and Laboratory Medicine Department, University of British Columbia, Vancouver.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Siteman Cancer Center Breast Cancer Program, Washington University School of Medicine, Saint Louis, MO, USA.
Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.



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.


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 <10% on AI). Over-representation analysis was performed using Webgestalt.


Thirty candidate genes positively correlated (r ≥ 0.4) with AI-resistant proliferation in Luminal B and were upregulated >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.


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.


Breast cancer; IDO1; LAG3; Luminal B breast cancer; PD1; STAT1; endocrine therapy resistance; estrogen receptor positive; immune checkpoints; immune tolerance; interferon-gamma; transcriptomics


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