The cytokine profile correlates with less tumor-infiltrating lymphocytes in luminal A breast cancer - Abstract and results

Q: What was the main purpose of this study?

To determine how immune-related cytokines and related factors in circulation correlate with tumor-infiltrating lymphocyte (TIL) levels in luminal A breast cancer, where immune mechanisms are not well understood.

Q: Which circulating factors were associated with TIL levels?

IL-1ra, IL-8, IL-12, IL-17, MIP-1b, and PDGF-bb concentrations were significantly associated with TIL levels.

Sep 21, 2026

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Luminal A breast cancer often exhibits low tumor-infiltrating lymphocyte (TIL) levels, yet the mechanisms remain unclear. This study examined immune-related cytokines, chemokines, and growth factors in the sera of 103 breast cancer patients using a multiplex panel, and assessed TILs in hotspot lesions. Specific circulating factors, including IL-1ra, IL-8, IL-12, IL-17, MIP-1b, and PDGF-bb, were associated with TIL levels. Hierarchical clustering generated six TIL-related clusters and revealed a luminal A–enriched cluster characterized by high IL-12/IL-17/PDGF-bb and low MIP-1b. The findings support a luminal A–associated immunosuppressive cytokine signature that may suppress TIL induction.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

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Abstract

Purpose

Methods

Results

Conclusion

Introduction

TILs in breast cancer prognosis

Immune editing and immunosuppression in luminal subtype

Cytokines, chemokines, and potential biomarkers

Breast Cancer Research and Treatment (2025) 209:291–302 [https://doi.org/10.1007/s10549-024-07492-7](https://doi.org/10.1007/s10549-024-07492-7) The cytokine profile correlates with less tumor‑infiltrating lymphocytes in luminal A breast cancer Eri Ishikawa1 · Takahiro Watanabe1,2 · Takako Kihara1 · Mamiko Kuroiwa3 · Miki Komatsu3 · Sayaka Urano3 · Masayuki Nagahashi3 · Seiichi Hirota1 · Yasuo Miyoshi3 Received: 7 March 2024 / Accepted: 5 September 2024 / Published online: 14 October 2024 © The Author(s) 2024 Abstract Purpose Tumor-infiltrating lymphocyte (TIL) levels are prognostic and predictive factors for breast cancer. Unlike other subtypes, most luminal A breast cancers are immune deserts; however, the underlying mechanisms are poorly understood. Methods Immune-related cytokines, chemokines, and growth factors were measured in the sera of 103 patients with breast cancer using a multiplex panel. The TILs were evaluated for hotspot lesions. Results Circulating interleukin 1 receptor antagonist (IL-1ra), IL-8, IL-12, IL-17, macrophage inflammatory protein-1β(MIP-1b), and platelet-derived growth factor B homodimer (PDGF-bb) concentrations were significantly associated with TIL levels. Cluster analysis using these six variables identified six clusters related to TIL levels. Breast cancers with high TILs (≥ 50%) were most frequent in cluster 3 (9 out of 15 cases, 60.0%), followed by cluster 1 (8 out of 34 cases, 23.5%), and the fewest in cluster 6 (1 out of 21 cases, 4.8%), whereas only one or three cases were present in clusters 2, 4, and 5 (p = 0.0064). Cluster 6, consisting mostly of luminal A (19 out of 21 cases, 90.5%), showed high levels of IL-12, IL-17, and PDGF-bb, and low levels of MIP-1b. Conclusion We identified a luminal A-associated immunosuppressive cytokine signature in circulation. These results suggest that a tumor microenvironment with high levels of IL-17 and PDGF-bb, and low levels of MIP-1b in luminal A breast cancers results in low induction of TILs. Our data may partially explain the low TIL levels observed in the patients with luminal A breast cancer. Keywords Breast cancer · Tumor-infiltrating lymphocytes · Cytokine · Chemokine · Hierarchical analysis Introduction The importance of tumor-infiltrating lymphocytes (TILs) as prognostic and predictive factors for breast cancer has been established [1, 2]. The positive association between an increase in TILs and favorable disease-free survival (DFS) was recognized in estrogen receptor (ER)-negative/human * Yasuo Miyoshi [ymiyoshi@hyo-med.ac.jp](ymiyoshi@hyo-med.ac.jp) 1 Department of Surgical Pathology, School of Medicine, Hyogo Medical University, Nishinomiya City, Hyogo, Japan 2 Department of Clinical Pathology, Chibune General Hospital, Osaka, Japan 3 Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, Mukogawa-Cho 1-1, Nishinomiya City, Hyogo 663-8501, Japan epidermal growth factor receptor 2 (HER2)-negative (triple negative; TN) and HER2-positive breast cancers (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.87–0.98], p = 0.011 and HR 0.94, 95% CI 0.89–0.99, p = 0.017, respectively), but not in luminal (ER-positive/HER2-negative) breast cancers (HR 1.02, 95% CI 0.96–1.09, p = 0.46) [3] . Several mechanisms are involved in the discrepant outcomes between luminal and non-luminal breast cancers, such as low levels of TILs in luminal breast cancers or the different roles of TILs in these subtypes. In a previous meta-analysis, a higher incidence of lymphocyte predominance (at least 50% or 60% TILs) was more prevalent in TN (20%, range 4–37%) and HER2-positive breast cancers (16%, range 11–24%) than in luminal breast cancers (6%, range 3–12%) [4] . Even in the luminal subtype, TIL levels in luminal B-like were significantly higher than those in luminal A-like (mean TILs, 6.1 vs 3.3%; TILs ≥ 5%, 28.0 vs 16.0%, p < 0.0001) [5] . These data support the hypothesis

FAQs

What was the main purpose of this study?

To determine how immune-related cytokines and related factors in circulation correlate with tumor-infiltrating lymphocyte (TIL) levels in luminal A breast cancer, where immune mechanisms are not well understood.

How were cytokines and related molecules measured?

Immune-related cytokines, chemokines, and growth factors were measured in the serum of 103 breast cancer patients using a multiplex panel.

Which circulating factors were associated with TIL levels?

IL-1ra, IL-8, IL-12, IL-17, MIP-1b, and PDGF-bb concentrations were significantly associated with TIL levels.

Sep 21, 2026

Uploaded by Aurelia