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The prognostic significance of peritumoral tertiary lymphoid structures in breast cancer

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Abstract

Tumors and their surrounding area represent spatially organized “ecosystems”, where tumor cells and the immune contextures of the different compartments are in a dynamic interplay, with potential clinical impact. Here, we aimed to investigate the prognostic significance of peritumoral tertiary lymphoid structures (TLS) either alone or jointly with the intratumoral densities and spatial distribution of CD8 + and CD163 + cells in breast cancer (BCa) patients. TLS were identified peritumorally, within the area distancing up to 5 mm from the infiltrative tumor border, counted and further characterized as adjacent or distal, in formalin-fixed, paraffin-embedded tumor tissue samples from a cohort of 167 patients, with histologically confirmed invasive ductal BCa. TLS and tumor-infiltrating immune cells were determined by H&E and immunohistochemistry. Clinical follow-up was available for 112 of these patients. Patients with peritumoral TLS exhibited worse disease-free survival (DFS) and overall survival (OS) as compared to patients lacking TLS. Moreover, the density of peritumoral TLS was found to be crucial for prognosis, since patients with abundant TLS exhibited the worst DFS and OS. By combining the density of adjacent TLS (aTLS) with our recently published intratumoral signatures based on the differential distribution of CD8 + and CD163 + in the tumor center and invasive margin, we created two improved immune signatures with superior prognostic strength and higher patient population coverage. Our observations strengthen the notion for the fundamental role of the dynamic interplay between the immune cells within the tumor microenvironment (center/invasive margin) and the tumor surrounding area (peritumoral TLS) on the clinical outcome of BCa patients.

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Abbreviations

AJCC:

American Joint Committee on Cancer

aTLS:

Adjacent tertiary lymphoid structure

BCa:

Breast cancer

DAB:

Diaminobenzidine

DFS:

Disease-free survival

dTLS:

Distant tertiary lymphoid structure

FCIS:

Favorable combined immune signature

FFPE:

Formalin fixed, paraffin embedded

HEV:

High endothelial venule

HH:

High/high

HL:

High/low

IM:

Invasive margin

LH:

Low/high

LL:

Low/low

RFCIS:

Reinforced favorable combined immune signature

RUCIS:

Reinforced unfavorable combined immune signature

SLO:

Secondary lymphoid organ

TC:

Tumor center

TLS:

Tertiary lymphoid structure

Treg:

T regulatory cell

UCIS:

Unfavorable combined immune signature

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Funding

This study was supported by Grant GER_1968 (acronym ISPEBREAST) to Constantin N. Baxevanis from the Greek–German bilateral cooperation for research and innovation, funded by the General Secretariat for Research and Technology (GSRT) of the Ministry of Education, Research and Religious Affairs of the Hellenic Republic and the German Federal Ministry for Education and Research (BMBF), and by a donation to Sonia Perez from the Haegeman-Goossens family, Netherlands. We would like to acknowledge the Haegeman-Goossens family for their support to our research.

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Author notes

  1. Michael Sofopoulos and Sotirios P. Fortis equally contributed as first authors.

Authors and Affiliations

  1. Pathology Department, Saint Savas Cancer Hospital, Athens, Greece

    Michael Sofopoulos, Nectaria N. Sotiriadou & Niki Arnogiannaki

  2. Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 11522, Athens, Greece

    Sotirios P. Fortis, Christoforos K. Vaxevanis, Sonia A. Perez & Constantin N. Baxevanis

  3. First Medical Oncology Clinic, Saint Savas Cancer Hospital, Athens, Greece

    Alexandros Ardavanis

  4. Department of Forensic Medicine and Toxicology, National and Kapodistrian University of Athens, Athens, Greece

    Dimitrios Vlachodimitropoulos

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  1. Michael Sofopoulos
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Contributions

MS and SPF equally contributed to study design, data collection, analysis and interpretation of results, and the writing the manuscript; CKV contributed to the study design, data collection, and interpretation of results; NNS contributed to data collection and analysis; AA and NA were responsible for the collection of patient material and clinical follow-up; DV contributed to data analysis and writing of the manuscript; SAP and CNB supervised the study, contributed to experimental design, data analysis, and wrote the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Constantin N. Baxevanis.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

The study was approved by the Institutional Review Board of Saint Savas Cancer Hospital, Study code: IRB-ID 6079/448/10-6-13. Date of approval: 10/06/2013; retrospective study (2000–2010); first patient prospectively enrolled: 14/2/2014.

Informed consent

Retrospectively analyzed (2000–2010) and prospectively enrolled patients (2014–2015) who signed the same informed consent. Individual participants provided written informed consent for the use of their specimens. In cases where retrospectively analyzed patients could not visit the hospital to provide signed informed consent, they were informed orally via telephone calls by their oncologists. Clinical data were obtained from all patients anonymously. Patients were assured that confidentiality of their records will be protected according to the Greek regulations and laws.

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Sofopoulos, M., Fortis, S.P., Vaxevanis, C.K. et al. The prognostic significance of peritumoral tertiary lymphoid structures in breast cancer. Cancer Immunol Immunother 68, 1733–1745 (2019). https://doi.org/10.1007/s00262-019-02407-8

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