Tertiary lymphoid structures (TLSs) are ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumours. Key common characteristics between secondary lymphoid organogenesis and TLS neogenesis have been identified. TLSs exist under different maturation states in tumours, culminating in germinal centre formation. The mechanisms that underlie the role of TLSs in the adaptive antitumour immune response are being deciphered. The description of the correlation between TLS presence and clinical benefit in patients with cancer, suggesting that TLSs could be a prognostic and predictive factor, has drawn strong interest into investigating the role of TLSs in tumours. A current major challenge is to exploit TLSs to promote lymphocyte infiltration, activation by tumour antigens and differentiation to increase the antitumour immune response. Several approaches are being developed using chemokines, cytokines, antibodies, antigen-presenting cells or synthetic scaffolds to induce TLS formation. Strategies aiming to induce TLS neogenesis in immune-low tumours and in immune-high tumours, in this case, in combination with therapeutic agents dampening the inflammatory environment and/or with immune checkpoint inhibitors, represent promising avenues for cancer treatment.
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The authors thank members of the Cancer and Immune Escape Team UMR_S1136 Cordeliers Research Centre for fruitful discussions and performing experiments, and L. Lacroix and A. Bougouin for help in preparing figure 1. This work was supported by Institut National Français de Recherche Médicale (INSERM), the University Paris Descartes, Sorbonne University, CARPEM T8, the Labex Immuno-Oncology Excellence Program, Institut du Cancer (INCa), HTE Plan Cancer (C1608DS to C.S.F.), PRTK G26 NIVOREN, Foncer contre le cancer, Bionik contracts and the Cartes d’Identité des Tumeurs (CIT) Program from the Ligue Nationale Contre le Cancer. F.P. was supported by a CARPEM doctorate fellowship, and J.C. was supported by an Association pour la Recherche sur le Cancer (ARC) postdoctoral fellowship.
Nature Reviews Cancer thanks J. Mule and the other anonymous reviewer(s) for their contribution to the peer review of this work.
C.S.-F. and W.H.F. are on the list of co-inventors on a patent application for the prognostic impact of tertiary lymphoid structures in patients with lung cancer (PCT-EP2016/070158). F.P. and J.C. declare no competing interests.
- CD8+ T effector memory cells
A subset of CD8+ T cells with cytotoxic or interferon-γ (IFNγ)-producing functions that provide a long-lasting immunity against previously encountered antigens.
- Secondary lymphoid organs
(SLOs). Organs such as the spleen, tonsils or lymph nodes that support antigen presentation to lymphoid cells to initiate and regulate the adaptive immune response.
- Germinal centre
A specialized compartment within lymphoid structures that promotes B cell proliferation, differentiation, affinity maturation through somatic hypermutation and class switch recombination.
- Somatic hypermutation
A process occurring during the maturation of B cells in germinal centres. Mutations occur in the variable regions of immunoglobulin heavy and light chains, enhancing affinity of the antibody for the antigen.
- Class switch recombination
Otherwise known as isotype switching; a mechanism that changes the isotype of immunoglobulin produced by B cells. The constant region of the heavy chain is modified, allowing different effector functions for antibodies, such as complement activation (immunoglobulin M (IgM) and IgG) and Fcγ receptor-dependent activation (IgG), to adapt the humoral response to the antigen stimulus.
- Follicular dendritic cells
(FDCs). Reticular cells found in the B cell area of lymphoid follicles. FDCs participate in the organization of the lymphoid structures and express Fcγ receptor and complement receptors. Binding of immunoglobulin G (IgG) antigen–antibody complexes on FDCs enables antigen presentation to B cells and selection of B cells expressing high-affinity antibodies.
- Tingible-body macrophages
A type of macrophage found in germinal centres; they are able to phagocytose apoptotic lymphoid cells. Their cytoplasm contains condensed chromatin fragments.
- Lymphoid tissue inducer cell
(LTi cell). A lymphoid cell that expresses and produces lymphotoxin-α and induces the formation of lymphoid tissue.
- Adrenal glands
Endocrine glands producing hormones that participate in the regulation of the immune system, metabolism and stress. These glands secrete notably cortisol, aldosterone and androgenic steroids.
- Breslow thickness
A measure in millimetres of the distance between the upper layer of epidermis and the deepest point of a tumour. This staging system is used as a prognostic factor for melanoma.
- Clark level of invasion
A staging method used conjointly with the Breslow thickness to describe the depth of melanoma tumour invasion into the skin.
- Evanescent prostate cancer
Prostate cancer with spontaneous regression.
- Fuhrman grades
Nuclear grades taking into account size and nuclear outline as well as nucleoli. These correlate with differentiation of tumour cells.
- Antibody-dependent cellular cytotoxicity
(ADCC). A process in which target cells are identified by antibodies, which are then recognized by the Fc receptor of natural killer cells and eliminated by cytotoxic molecule release.
- Immunological ignorance
A phenomenon associated with immune cold tumour phenotypes in which tumour antigens are not immunogenic or are not presented to lymphocytes to raise an immune response.
A protein that is physiologically present in mesothelial cells. This protein is immunogenic and overexpressed in several human cancers including pancreatic and lung adenocarcinoma and ovarian cancer and can be used as a tumour marker.
- Fibroblastic reticular cells
(FRCs). Specialized stromal cells localized in the T cell zone of the lymph nodes and of tertiary lymphoid structures. FRCs interact with the microenvironment to regulate T cells.
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Sautès-Fridman, C., Petitprez, F., Calderaro, J. et al. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 19, 307–325 (2019). https://doi.org/10.1038/s41568-019-0144-6
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