Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Tertiary lymphoid structures are associated with higher tumor grade in primary operable breast cancer patients

Authors: Stine L Figenschau, Silje Fismen, Kristin A Fenton, Christopher Fenton, Elin S Mortensen

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

Tertiary lymphoid structures (TLS) are highly organized immune cell aggregates that develop at sites of inflammation or infection in non-lymphoid organs. Despite the described role of inflammation in tumor progression, it is still unclear whether the process of lymphoid neogenesis and biological function of ectopic lymphoid tissue in tumors are beneficial or detrimental to tumor growth. In this study we analysed if TLS are found in human breast carcinomas and its association with clinicopathological parameters.

Methods

In a patient group (n = 290) who underwent primary surgery between 2011 and 2012 we assessed the interrelationship between the presence of TLS in breast tumors and clinicopathological factors. Prognostic factors were entered into a binary logistic regression model for identifying independent predictors for intratumoral TLS formation.

Results

There was a positive association between the grade of immune cell infiltration within the tumor and important prognostic parameters such as hormone receptor status, tumor grade and lymph node involvement. The majority of patients with high grade infiltration of immune cells had TLS positive tumors. In addition to the degree of immune cell infiltration, the presence of TLS was associated with organized immune cell aggregates, hormone receptor status and tumor grade. Tumors with histological grade 3 were the strongest predictor for the presence of TLS in a multivariate regression model. The model also predicted that the odds for having intratumoral TLS formation were ten times higher for patients with high grade of inflammation than low grade.

Conclusions

Human breast carcinomas frequently contain TLS and the presence of these structures is associated with aggressive forms of tumors. Locally generated immune response with potentially antitumor immunity may control tumorigenesis and metastasis. Thus, defining the role of TLS formation in breast carcinomas may lead to alternative therapeutic approaches targeting the immune system.
Literature
1.
Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.CrossRefPubMed
2.
Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol. 2006;6:205–17.CrossRefPubMed
3.
Drayton DL, Liao S, Mounzer RH, Ruddle NH. Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol. 2006;7:344–53.CrossRefPubMed
4.
van de Pavert SA, Mebius RE. New insights into the development of lymphoid tissues. Nat Rev Immunol. 2010;10:664–74.CrossRefPubMed
5.
DeNardo DG, Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res. 2007;9:212.CrossRefPubMedPubMedCentral
6.
Coronella JA, Spier C, Welch M, Trevor KT, Stopeck AT, Villar H, et al. Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J Immunol (Baltimore, Md: 1950). 2002;169:1829–36.CrossRef
7.
Coronella JA, Telleman P, Kingsbury GA, Truong TD, Hays S, Junghans RP. Evidence for an antigen-driven humoral immune response in medullary ductal breast cancer. Cancer Res. 2001;61:7889–99.PubMed
8.
Nzula S, Going JJ, Stott DI. Antigen-driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinomas. Cancer Res. 2003;63:3275–80.PubMed
9.
Coronella-Wood JA, Hersh EM. Naturally occurring B-cell responses to breast cancer. Cancer Immunol Immunother. 2003;52:715–38.CrossRefPubMed
10.
Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:4410–7.CrossRef
11.
de Chaisemartin L, Goc J, Damotte D, Validire P, Magdeleinat P, Alifano M, et al. Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res. 2011;71:6391–9.CrossRefPubMed
12.
Coppola D, Nebozhyn M, Khalil F, Dai H, Yeatman T, Loboda A, et al. Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling. Am J Pathol. 2011;179:37–45.CrossRefPubMedPubMedCentral
13.
14.
Cipponi A, Mercier M, Seremet T, Baurain JF, Theate I, van den Oord J, et al. Neogenesis of lymphoid structures and antibody responses occur in human melanoma metastases. Cancer Res. 2012;72:3997–4007.CrossRefPubMed
15.
Messina JL, Fenstermacher DA, Eschrich S, Qu X, Berglund AE, Lloyd MC, et al. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci Rep. 2012;2:765.CrossRefPubMedPubMedCentral
16.
Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O’Fallon WM, et al. Lymphoid neogenesis in rheumatoid synovitis. J Immunol (Baltimore, Md: 1950). 2001;167:1072–80.CrossRef
17.
Manzo A, Paoletti S, Carulli M, Blades MC, Barone F, Yanni G, et al. Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur J Immunol. 2005;35:1347–59.CrossRefPubMed
18.
Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmstrom P, Wahren-Herlenius M, et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren’s syndrome. Arthritis Rheum. 2003;48:3187–201.CrossRefPubMed
19.
Barone F, Bombardieri M, Manzo A, Blades MC, Morgan PR, Challacombe SJ, et al. Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjogren’s syndrome. Arthritis Rheum. 2005;52:1773–84.CrossRefPubMed
20.
Mazzucchelli L, Blaser A, Kappeler A, Scharli P, Laissue JA, Baggiolini M, et al. BCA-1 is highly expressed in Helicobacter pylori-induced mucosa-associated lymphoid tissue and gastric lymphoma. J Clin Invest. 1999;104:R49–54.CrossRefPubMedPubMedCentral
21.
Winter S, Loddenkemper C, Aebischer A, Rabel K, Hoffmann K, Meyer TF, et al. The chemokine receptor CXCR5 is pivotal for ectopic mucosa-associated lymphoid tissue neogenesis in chronic Helicobacter pylori-induced inflammation. J Mol Med (Berlin, Germany). 2010;88:1169–80.CrossRef
22.
Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, et al. CD4(+) follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013;123:2873–92.CrossRefPubMedPubMedCentral
23.
Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 2011;71:5678–87.CrossRefPubMed
24.
Lal P, Tan LK, Chen B. Correlation of HER-2 status with estrogen and progesterone receptors and histologic features in 3,655 invasive breast carcinomas. Am J Clin Pathol. 2005;123:541–6.CrossRefPubMed
25.
Lee AH, Gillett CE, Ryder K, Fentiman IS, Miles DW, Millis RR. Different patterns of inflammation and prognosis in invasive carcinoma of the breast. Histopathology. 2006;48:692–701.CrossRefPubMed
26.
Mohammed ZM, Going JJ, Edwards J, Elsberger B, Doughty JC, McMillan DC. The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer. Br J Cancer. 2012;107:864–73.CrossRefPubMedPubMedCentral
27.
Mohammed ZM, Going JJ, Edwards J, Elsberger B, McMillan DC. The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer. Br J Cancer. 2013;109:1676–84.CrossRefPubMedPubMedCentral
28.
Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949–55.CrossRefPubMed
29.
Mahmoud S, Lee A, Ellis I, Green A. CD8(+) T lymphocytes infiltrating breast cancer: A promising new prognostic marker? Oncoimmunol. 2012;1:364–5.CrossRef
30.
Nelson BH. CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol (Baltimore, Md: 1950). 2010;185:4977–82.CrossRef
31.
Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat. 2012;132:545–53.CrossRefPubMed
32.
Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68:5405–13.CrossRefPubMed
33.
Mohammed ZM, Going JJ, Edwards J, McMillan DC. The role of the tumour inflammatory cell infiltrate in predicting recurrence and survival in patients with primary operable breast cancer. Cancer Treat Rev. 2012;38:943–55.CrossRefPubMed
34.
35.
Bell D, Chomarat P, Broyles D, Netto G, Harb GM, Lebecque S, et al. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med. 1999;190:1417–26.CrossRefPubMedPubMedCentral
36.
Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 2009;69:2000–9.CrossRefPubMed
37.
Martinet L, Filleron T, Le Guellec S, Rochaix P, Garrido I, Girard JP. High endothelial venule blood vessels for tumor-infiltrating lymphocytes are associated with lymphotoxin beta-producing dendritic cells in human breast cancer. J Immunol (Baltimore, Md: 1950). 2013;191:2001–8.CrossRef
38.
Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van der Vijver MJ. World Health Organization Classification of Tumours of the breast. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC); 2012.
39.
Silverstein MJ, Lagios MD, Craig PH, Waisman JR, Lewinsky BS, Colburn WJ, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer. 1996;77:2267–74.CrossRefPubMed
40.
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19:403–10.CrossRefPubMed
41.
Goc J, Fridman WH, Sautes-Fridman C, Dieu-Nosjean MC. Characteristics of tertiary lymphoid structures in primary cancers. Oncoimmunology. 2013;2:e26836.CrossRefPubMedPubMedCentral
42.
Ben-Hur H, Cohen O, Schneider D, Gurevich P, Halperin R, Bala U, et al. The role of lymphocytes and macrophages in human breast tumorigenesis: an immunohistochemical and morphometric study. Anticancer Res. 2002;22:1231–8.PubMed
43.
Bilik R, Mor C, Hazaz B, Moroz C. Characterization of T-lymphocyte subpopulations infiltrating primary breast cancer. Cancer Immunol Immunother. 1989;28:143–7.CrossRefPubMed
44.
Tesar BM, Chalasani G, Smith-Diggs L, Baddoura FK, Lakkis FG, Goldstein DR. Direct antigen presentation by a xenograft induces immunity independently of secondary lymphoid organs. J Immunol (Baltimore, Md: 1950). 2004;173:4377–86.CrossRef
45.
Kirk CJ, Hartigan-O’Connor D, Mule JJ. The dynamics of the T-cell antitumor response: chemokine-secreting dendritic cells can prime tumor-reactive T cells extranodally. Cancer Res. 2001;61:8794–802.PubMed
46.
Schrama D, Thor Straten P, Fischer WH, McLellan AD, Brocker EB, Reisfeld RA, et al. Targeting of lymphotoxin-alpha to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity. 2001;14:111–21.CrossRefPubMed
47.
Schrama D, Voigt H, Eggert AO, Xiang R, Zhou H, Schumacher TN, et al. Immunological tumor destruction in a murine melanoma model by targeted LTalpha independent of secondary lymphoid tissue. Cancer Immunol Immunother. 2008;57:85–95.CrossRefPubMed
48.
Goc J, Germain C, Vo-Bourgais TK, Lupo A, Klein C, Knockaert S, et al. Dendritic Cells in Tumor-Associated Tertiary Lymphoid Structures Signal a Th1 Cytotoxic Immune Contexture and License the Positive Prognostic Value of Infiltrating CD8+ T Cells. Cancer Res. 2014;74:705–15.CrossRefPubMed
49.
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science (New York, NY). 2011;331:1565–70.CrossRef
50.
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–8.CrossRefPubMed
51.
Shields JD, Kourtis IC, Tomei AA, Roberts JM, Swartz MA. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science (New York, NY). 2010;328:749–52.CrossRef
52.
Tan TT, Coussens LM. Humoral immunity, inflammation and cancer. Curr Opin Immunol. 2007;19:209–16.CrossRefPubMed
53.
Ciampricotti M, Vrijland K, Hau CS, Pemovska T, Doornebal CW, Speksnijder EN, et al. Development of metastatic HER2(+) breast cancer is independent of the adaptive immune system. J Pathol. 2011;224:56–66.CrossRefPubMed
Metadata
Title
Tertiary lymphoid structures are associated with higher tumor grade in primary operable breast cancer patients
Authors
Stine L Figenschau
Silje Fismen
Kristin A Fenton
Christopher Fenton
Elin S Mortensen
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1116-1

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

Risk factors of PSA progression and overall survival in patients with localized and locally advanced prostate cancer treated with primary androgen deprivation therapy

Research article

Occupational exposure and sinonasal cancer: a systematic review and meta-analysis

Research article

Meta-analysis of the prognostic value of circulating tumor cells detected with the CellSearch System in colorectal cancer

Research article

Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer

Research article

microRNA-34a inhibits epithelial mesenchymal transition in human cholangiocarcinoma by targeting Smad4 through transforming growth factor-beta/Smad pathway

Research article

Risk of fracture in men with prostate cancer on androgen deprivation therapy: a population-based cohort study in New Zealand
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits