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08.04.2019 | Breast Oncology

Tumor Heterogeneity Correlates with Less Immune Response and Worse Survival in Breast Cancer Patients

Zeitschrift:
Annals of Surgical Oncology
Autoren:
MD Kerry-Ann McDonald, MD, PhD Tsutomu Kawaguchi, Qianya Qi, Xuan Peng, MD Mariko Asaoka, MD Jessica Young, MD, PhD Mateusz Opyrchal, PhD Li Yan, MD, PhD Santosh Patnaik, MD, PhD Eigo Otsuji, MD, PhD, FACS Kazuaki Takabe
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1245/​s10434-019-07338-3) contains supplementary material, which is available to authorized users.
Kerry-Ann McDonald and Tsutomu Kawaguchi contributed equally to this work.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abstract

Background

Intratumor heterogeneity implies that subpopulations of cancer cells that differ in genetic, phenotypic, or behavioral characteristics coexist in a single tumor (Ma in Breast Cancer Res Treat 162(1):39–48, 2017; Martelotto in Breast Cancer Res 16(3):210, 2014). Tumor heterogeneity drives progression, metastasis and treatment resistance, but its relationship with tumor infiltrating immune cells is a matter of debate, where some argue that tumors with high heterogeneity may generate neoantigens that attract immune cells, and others claim that immune cells provide selection pressure that shapes tumor heterogeneity (McGranahan et al. in Science 351(6280):1463–1469, 2016; McGranahan and Swanton in Cell 168(4):613–628, 2017). We sought to study the association between tumor heterogeneity and immune cells in a real-world cohort utilizing The Cancer Genome Atlas.

Methods

Mutant allele tumor heterogeneity (MATH) was calculated to estimate intratumoral heterogeneity, and immune cell compositions were estimated using CIBERSORT. Survival analyses were demonstrated using Kaplan–Meir curves.

Results

Tumors with high heterogeneity (high MATH) were associated with worse overall survival (p = 0.049), as well as estrogen receptor-positive (p = 0.011) and non-triple-negative tumors (p = 0.01). High MATH tumors were also associated with less infiltration of anti-tumor CD8 (p < 0.013) and CD4 T cells (p < 0.00024), more tumor-promoting regulatory T cells (p < 4e−04), lower expression of T-cell exhaustion markers, specifically PDL-1 (p = 0.0031), IDO2 (p = 0.34), ADORA2A (p = 0.018), VISTA (p = 0.00013), and CCR4 (p < 0.00001), lower expression of cytolytic enzymes granzyme A (p = 0.0056) and perforin 1 (p = 0.053), and low cytolytic activity score (p = 0.0028).

Conclusions

High heterogeneity tumors are associated with less immune cell infiltration, less activation of the immune response, and worse survival in breast cancer. Our results support the notion that tumor heterogeneity is shaped by selection pressure of tumor-infiltrating immune cells.

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Zusatzmaterial
FIG. S1 MATH level and patient survival for HER2-positive and -negative breast cancers in the (a) TCGA and (b) PAM50 cohorts. MATH mutant allele tumor heterogeneity, HER2 human epidermal growth factor receptor 2, TCGA The Cancer Genome Atlas (TIFF 288 kb)
10434_2019_7338_MOESM1_ESM.tif
Literatur
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