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

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: Meenakshi Anurag, Mayanne Zhu, Chen Huang, Suhas Vasaikar, Junkai Wang, Jeremy Hoog, Samantha Burugu, Dongxia Gao, Vera Suman, Xiang H Zhang, Bing Zhang, Torsten Nielsen, Matthew J Ellis
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 112 Issue 7 Pg. 737-746 (07 01 2020) ISSN: 1460-2105 [Electronic] United States
• PMID: 31665365 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• 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

Topics

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