Trends in Immunology
Volume 35, Issue 11, November 2014, Pages 571-580
Journal home page for Trends in Immunology

Review
Tertiary lymphoid structures in cancer and beyond

https://doi.org/10.1016/j.it.2014.09.006Get rights and content

Highlights

Tertiary lymphoid structures (TLS) are ectopic lymphoid formations found in inflamed, infected, or tumoral tissues. They exhibit all the characteristics of structures in the lymph nodes (LN) associated with the generation of an adaptive immune response, including a T cell zone with mature dendritic cells (DC), a germinal center with follicular dendritic cells (FDC) and proliferating B cells, and high endothelial venules (HEV). In this review, we discuss evidence for the roles of TLS in chronic infection, autoimmunity, and cancer, and address the question of whether TLS present beneficial or deleterious effects in these contexts. We examine the relationship between TLS in tumors and patient prognosis, and discuss the potential role of TLS in building and/or maintaining local immune responses and how this understanding may guide therapeutic interventions.

Introduction

That adaptive immune responses against infectious agents, grafted organs and, in some cases, tumors are generated in secondary lymphoid organs (SLO), particularly in the LN draining the pathological sites, has been extensively documented and is broadly accepted. In recent years, however, increasing evidence suggests that specific immune reactions may also be generated outside SLO, directly in the tissues where the infection, the graft, or the tumor is present.

A first set of observations supporting this hypothesis comes from studies of the immune responses in lower vertebrates ontogenically lacking LN [1]. The emergence of LN in mammals and in some bird species dates to ∼200 million years ago. In contrast, lymphoid structures associated with the gut (gut associated lymphoid tissues – GALT) appear much earlier in evolution, being present in cartilaginous fishes, such as sharks, where they appear to play a role in the generation of adaptive immune responses. GALT are induced by external stimuli and exhibit most features associated with ectopic lymphoid structures found in mammals. They may represent the most ancient examples of TLS during the evolution of vertebrates (defining characteristics of TLS are discussed in Box 1). Interestingly, the genesis of TLS and LN is based on the participation of the same set of molecules [i.e., lymphotoxin (LT)-α and LT–β; lymphoid chemokines CCL19, CCL21, and CXCL13; tumor necrosis factor-alpha (TNF-α); and RANK ligand].

A second set of observations in support of the notion that specific immune reactions may also be generated directly in the tissue harboring the insult comes from studies of mice devoid of LN, spleen, and Peyer's patches. Infection of such mice with the influenza virus induces the neogenesis of lung TLS; importantly, these mice are able to generate protective primary and secondary immune responses as efficient as those generated in their wild type counterparts 2, 3. These findings argue that SLO are dispensable for the generation of robust primary and memory immune responses.

A third line of evidence comes from the analysis of human pathologies. TLS are induced in the case of chronic infections, graft rejection, autoimmune inflammatory diseases, and cancers, and correlate with disease evolution, as discussed further below. These varied lines of evidence support the notion that immune responses to specific pathogen or inflammatory challenges may occur in TLS.

In this review, we explore two main questions:

  • (i)

    What is the impact of TLS at sites of chronic infection and inflammation? Depending on the context, TLS may be associated with resolution or exacerbation of the disease, and we discuss these different possibilities.

  • (ii)

    What are the roles of TLS in cancer? We examine evidence that associates the presence of TLS with both beneficial and deleterious outcomes in different types of cancers, and discuss how TLS could impact response to therapies. An improved understanding of the role of TLS and the immune response within tumors may help guide treatment decisions and provide insights leading to more effective therapeutic approaches.

Section snippets

TLS and allograft rejection

Chronic alloimmune responses occurring in murine cardiac allografts [4], rat aortic transplants [5], kidney [6], or skin transplants [7] induce TLS neogenesis. TLS presence is associated with chronic rejection [4], and both effector and memory T cell responses capable of perpetuating the rejection process can be generated in these structures [7]. In humans, TLS were detected in chronically rejected kidney and heart grafts 5, 8, and the presence of TLS has been shown to correlate with chronic

Tertiary lymphoid structures in cancer

The tumor microenvironment presents many analogies to settings of chronic inflammation, but exhibits profound immunosuppressive characteristics including infiltration of regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells (reviewed in 34, 35). This specific feature, as compared with other chronic inflammatory contexts, raises the question: can lymphoid neogenesis occur in immunosuppressive microenvironments, such as those found in tumors?

Concluding remarks

TLS are found in tissues in many pathological situations which have in common the presence of an ongoing chronic inflammation. It is still a matter of debate whether they are only witnesses of the inflammatory milieu or whether they are sites where adaptive immune reactions against the local tissue components are generated or reactivated. Although correlative, the observations that TLS high densities correlate with graft rejection, auto-immune disease aggravation or, conversely, with longer

Acknowledgments

We wish to acknowledge the work of Romain Remark, Diane Damotte and Marco Alifano, who generated some of the data depicted in Figure 2 in addition to the work referenced in 62 (Remark, R. et al. (2013) Clin. Cancer Res. 19, 4079-4091). We also wish to acknowledge the participation of other members of the laboratory, clinicians and pathologies who participated in the articles referenced in our review. This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM),

References (83)

  • T. Boehm

    Evolution of the immune system in the lower vertebrates

    Annu. Rev. Genomics Hum. Genet.

    (2012)
  • J.E. Moyron-Quiroz

    Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity

    Nat. Med.

    (2004)
  • O. Thaunat

    Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response

    Proc. Natl. Acad. Sci. U.S.A.

    (2005)
  • D. Kerjaschki

    Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates

    J. Am. Soc. Nephrol.

    (2004)
  • C. Deteix

    Intragraft Th17 infiltrate promotes lymphoid neogenesis and hastens clinical chronic rejection

    J. Immunol.

    (2010)
  • D. Lucchesi et al.

    The role of viruses in autoreactive B cell activation within tertiary lymphoid structures in autoimmune diseases

    J. Leukoc. Biol.

    (2013)
  • Y. Takahashi

    Primary and secondary B-cell responses to pulmonary virus infection

    Infect. Disord. Drug Targets

    (2012)
  • P.J. Maglione

    B cells moderate inflammatory progression and enhance bacterial containment upon pulmonary challenge with Mycobacterium tuberculosis

    J. Immunol.

    (2007)
  • S.A. Khader

    In a murine tuberculosis model, the absence of homeostatic chemokines delays granuloma formation and protective immunity

    J. Immunol.

    (2009)
  • S. Halle

    Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells

    J. Exp. Med.

    (2009)
  • S. Winter

    The chemokine receptor CXCR5 is pivotal for ectopic mucosa-associated lymphoid tissue neogenesis in chronic Helicobacter pylori-induced inflammation

    J. Mol. Med.

    (2010)
  • J. Murakami

    Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C

    Hepatology

    (1999)
  • L. Mazzucchelli

    BCA-1 is highly expressed in Helicobacter pylori-induced mucosa-associated lymphoid tissue and gastric lymphoma

    J. Clin. Invest.

    (1999)
  • M.A. Minutello

    Compartmentalization of T lymphocytes to the site of disease: intrahepatic CD4+ T cells specific for the protein NS4 of hepatitis C virus in patients with chronic hepatitis C

    J. Exp. Med.

    (1993)
  • G. Pei

    Renal interstitial infiltration and tertiary lymphoid organ neogenesis in IgA nephropathy

    Clin. J. Am. Soc. Nephrol.

    (2014)
  • A. Manzo

    Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis

    Eur. J. Immunol.

    (2005)
  • G. Page

    Anatomic localization of immature and mature dendritic cells in an ectopic lymphoid organ: correlation with selective chemokine expression in rheumatoid synovium

    J. Immunol.

    (2002)
  • F. Humby

    Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium

    PLoS Med.

    (2009)
  • A.H.M. Van der Helm-van Mil

    Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis

    Arthritis Res. Ther.

    (2005)
  • F. Barone

    Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren's syndrome

    Arthritis Rheum.

    (2005)
  • F. Barone

    CXCL13, CCL21, and CXCL12 expression in salivary glands of patients with Sjögren's syndrome and MALT lymphoma: association with reactive and malignant areas of lymphoid organization

    J. Immunol.

    (2008)
  • M. Bombardieri

    Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjögren's syndrome

    J. Immunol.

    (2007)
  • E. Theander

    Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren's syndrome

    Ann. Rheum. Dis.

    (2011)
  • R. Magliozzi

    Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology

    Brain

    (2007)
  • S. Takemura

    Lymphoid neogenesis in rheumatoid synovitis

    J. Immunol.

    (2001)
  • T.C.G. Timmer

    Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: identification of the interleukin-7 signaling pathway in tissues with lymphoid neogenesis

    Arthritis Rheum.

    (2007)
  • N. Amft

    Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjögren's syndrome

    Arthritis Rheum.

    (2001)
  • B. Serafini

    Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis

    Brain Pathol.

    (2004)
  • M-P. Armengol

    Chemokines determine local lymphoneogenesis and a reduction of circulating CXCR4+ T and CCR7 B and T lymphocytes in thyroid autoimmune diseases

    J. Immunol.

    (2003)
  • R.D. Schreiber

    Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion

    Science

    (2011)
  • W.H. Fridman

    The immune microenvironment: a major player in human cancers

    Int. Arch. Allergy Immunol.

    (2014)
  • Cited by (0)

    View full text