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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).

Author information

1
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
2
Department of Medicine, Baylor College of Medicine, Houston, Texas.
3
Genetic Pathology Evaluation Centre; University of British Columbia, Vancouver.
4
Pathology and Laboratory Medicine Department, University of British Columbia, Vancouver.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
6
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
7
Siteman Cancer Center Breast Cancer Program, Washington University School of Medicine, Saint Louis, MO, USA.
8
Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.

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 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.

RESULTS:

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.

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.

KEYWORDS:

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

PMID:
31665365
DOI:
10.1093/jnci/djz213

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