Cancer-Associated Tertiary Lymphoid Structures, from Basic Knowledge Toward Therapeutic Target in Clinic

  • Bertrand Dubois
  • Hélène Kaplon
  • Coline Couillault
  • Christophe Caux
  • Marie-Caroline Dieu-NosjeanEmail author
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 9)


The tumor growth is under the control of the immune system, and this represents a significant challenge for the development of new therapeutic strategies. It is now recognized that not only the density, but also the organization of tumor-infiltrating immune cells is critical for the shaping of the tumor microenvironment. In human cancers, several levels of structuration of lymphoid aggregates have been observed, including Tertiary Lymphoid Structures (TLS) displaying strong similarities with secondary lymphoid organs. In this review, we discuss about the role of immune cells homing selectively in the T-cell or B-cell zone of TLS with putative consequences on the initiation of efficient cellular and humoral immune responses against tumor, and ultimately on the clinical outcome of cancer patients. However, immunoregulatory cells may also infiltrate TLS and it is thus crucial to determine the circumstances in which TLS might be a site for the development of a suppressive and detrimental immune responses. We also discuss how TLS could be a useful marker of efficient immunotherapy, and raise the question of the capacity of immune-based vaccinations along with immune checkpoint blockade to induce TLS neogenesis. As TLS may represent the best place to induce or amplify protective immunity targeting neoantigens, TLS may be a promising target in order to boost anti-tumoral immunity in cancer patients.


Tumor microenvironment Tertiary lymphoid structure Dendritic cell T cell Antibody Immune checkpoint Biomarker Immunointervention High endothelial venule Neoantigen 





Antibody-Dependent Cell-mediated Cytotoxicity




Activation-Induced cytidine Deaminase


Antigen-Presenting Cell


B-Cell Receptor


Clear cell Renal Cell Carcinoma


Complement-Dependent Cytotoxicity


Cervical Intraepithelial Neoplasia


Colorectal Cancer


Class Switch Recombination


Cytotoxic T lymphocyte


Dendritic Cell


Fc Receptor


Neonatal Fc Receptor


Gut-Associated Lymphoid Tissue


Germinal Center


GM-CSF transfected tumor cell vaccine


Granulocyte Macrophage Colony-Stimulating Factor


Hepatitis C Virus


High Endothelial Venule


Human Papilloma Virus


Immune CheckPoint




Lymph Node


Major Histocompatibility Complex


Natural Killer cell


Non-Small Cell Lung Cancer


Prostate Acid Phosphatase




Plasma Cell


Pancreatic Ductal Adenocarcinoma


Renal Cell Carcinoma


Squamous Cell Carcinoma


Somatic HyperMutation


Secondary Lymphoid Organ


Tumor-Associated Antigen


Central-Memory T cell


T-Cell Receptor


Effector-memory T cell


Follicular Helper T cell


Tertiary Lymphoid Structure


Regulatory T cell



We wish to acknowledge the participation of members of the laboratories among whom Prs. C. Sautès-Fridman and W. H. Fridman, clinicians, and pathologists who participated in the articles referenced in our review.

Conflict statement: No potential conflicts of interest were disclosed.

Grants: This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris Descartes, University Pierre et Marie Curie, SIRIC Cancer Research and Personalized Medicine (CARPEM), the LabeX Immuno-Oncology, Institut National du Cancer (INCa) and Canceropôle Ile-de-France, Fondation ARC pour la Recherche sur le Cancer, MedImmune, the LABEX DEVWECAN (ANR-10-LABX-0061) of University of Lyon, the program “Investissements d’Avenir” (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR), and the SIRIC project (LYRIC, Grant No. INCa-4664). Hélène Kaplon was supported by a grant from La Ligue contre le Cancer.


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Bertrand Dubois
    • 1
    • 2
  • Hélène Kaplon
    • 3
    • 4
    • 5
  • Coline Couillault
    • 1
    • 2
  • Christophe Caux
    • 1
    • 2
    • 6
  • Marie-Caroline Dieu-Nosjean
    • 3
    • 4
    • 5
    Email author
  1. 1.Lyon UniversityLyonFrance
  2. 2.INSERM U1052 CNRS UMR5286, Centre de Recherche en Cancérologie de LyonLyonFrance
  3. 3.Laboratory “Cancer, Immune Control, and Escape”, INSERM UMRS1138, Cordeliers Research CenterParisFrance
  4. 4.Sorbonne University, Pierre and Marie Curie University, UMRS1138ParisFrance
  5. 5.Sorbonne Paris Cité University, Paris Descartes University, UMRS1138ParisFrance
  6. 6.Centre Léon BérardLyonFrance

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