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Int. J. Mol. Sci. 2017, 18(9), 1936; doi:10.3390/ijms18091936

Morphological Evaluation of Tumor-Infiltrating Lymphocytes (TILs) to Investigate Invasive Breast Cancer Immunogenicity, Reveal Lymphocytic Networks and Help Relapse Prediction: A Retrospective Study

1
School of Life & Health Sciences, Aston Brain Centre, Aston University, Birmingham B4 7ET, UK
2
Department of Radiology and Neuroradiology, Klinikum Dortmund, 44137 Dortmund, Germany
3
Department of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, 24105 Campus Kiel, Germany
4
Fertility Center Kiel, 24103 Kiel, Germany
5
Department of Pathology, General Pathology and Hematopathology, University Hospitals Schleswig-Holstein, 24105 Campus Kiel, Germany
*
Authors to whom correspondence should be addressed.
Received: 17 July 2017 / Revised: 31 August 2017 / Accepted: 31 August 2017 / Published: 8 September 2017
(This article belongs to the Special Issue Cancer Stem Cells)
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Abstract

Tumor-infiltrating lymphocytes (TILs) in breast cancer are a key representative of the tumor immune microenvironment and have been shown to provide prognostic and predictive biomarkers. The extent of lymphocytic infiltration in tumor tissues can be assessed by evaluating hematoxylin and eosin (H&E)-stained tumor sections. We investigated tissue microarrays of 31 invasive breast cancer patients, looking at quantity and topological distribution of CD3+, CD8+, CD20+, Ki67+, FoxP3+ TILs and CD3+/FoxP3+, CD8+/FoxP3+ cell ratios. We separately evaluated TILs at the invasive edge and at the center of the tumor, to find any clinical implications of tumor heterogeneity. No statistically significant difference was found in quantity and distribution of both TIL subsets and TIL ratios, by comparing patients who suffered from a local or distant recurrence of the tumor (relapse group: 13 patients) with patients not showing cancer relapse (non-relapse group: 18 patients). In the whole sample, we observed three main statistically significant positive correlations: (1) between CD3+ and CD8+ T-cells; (2) between FoxP3+ and Ki67+ lymphocyte infiltration; (3) between CD3+/FoxP3+ cell ratio (C3FR) and CD8+/FoxP3+ cell ratio (C8FR). Tumor heterogeneity and stronger positive TIL associations were found in the non-relapse group, where both CD3–CD8 and FoxP3-Ki67 inter-correlations were found to be significant at the center of the tumor, while the correlation between C3FR and C8FR was significant at the invasive edge. No correlations between TIL subsets were detected in the relapse group. Our findings suggest the existence of stronger inter-subtype lymphocytic networks in invasive breast cancer not showing recurrence. Further evaluations of clinical and topological correlations between and within TIL subsets are needed, in addition to the assessment of TIL quantification and distribution, in order to follow up on whether morphological evaluation of TILs might reveal the underlying lymphocytic functional connectivity and help relapse prediction. View Full-Text
Keywords: breast cancer; tumor-infiltrating lymphocytes (TILs); tumor heterogeneity; tumor immunogenicity; CD3; CD8; FoxP3; regulatory T cells (Tregs); CD8/FoxP3 ratio; CD3/FoxP3 ratio breast cancer; tumor-infiltrating lymphocytes (TILs); tumor heterogeneity; tumor immunogenicity; CD3; CD8; FoxP3; regulatory T cells (Tregs); CD8/FoxP3 ratio; CD3/FoxP3 ratio
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Romagnoli, G.; Wiedermann, M.; Hübner, F.; Wenners, A.; Mathiak, M.; Röcken, C.; Maass, N.; Klapper, W.; Alkatout, I. Morphological Evaluation of Tumor-Infiltrating Lymphocytes (TILs) to Investigate Invasive Breast Cancer Immunogenicity, Reveal Lymphocytic Networks and Help Relapse Prediction: A Retrospective Study. Int. J. Mol. Sci. 2017, 18, 1936.

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