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B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome

Nature Reviews Clinical Oncology volume 19, pages 441–457 (2022)Cite this article

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Abstract

B cells are a major component of the tumour microenvironment, where they are predominantly associated with tertiary lymphoid structures (TLS). In germinal centres within mature TLS, B cell clones are selectively activated and amplified, and undergo antibody class switching and somatic hypermutation. Subsequently, these B cell clones differentiate into plasma cells that can produce IgG or IgA antibodies targeting tumour-associated antigens. In tumours without mature TLS, B cells are either scarce or differentiate into regulatory cells that produce immunosuppressive cytokines. Indeed, different tumours vary considerably in their TLS and B cell content. Notably, tumours with mature TLS, a high density of B cells and plasma cells, as well as the presence of antibodies to tumour-associated antigens are typically associated with favourable clinical outcomes and responses to immunotherapy compared with those lacking these characteristics. However, polyclonal B cell activation can also result in the formation of immune complexes that trigger the production of pro-inflammatory cytokines by macrophages and neutrophils. In complement-rich tumours, IgG antibodies can also activate the complement cascade, resulting in the production of anaphylatoxins that sustain tumour-promoting inflammation and angiogenesis. Herein, we review the phenotypic heterogeneity of intratumoural B cells and the importance of TLS in their generation as well as the potential of B cells and TLS as prognostic and predictive biomarkers. We also discuss novel therapeutic approaches that are being explored with the aim of increasing mature TLS formation, B cell differentiation and anti-tumour antibody production within tumours.

Key points

  • B cells are a major component of the tumour microenvironment (TME) in many cancers; all major B cell subsets, from naive B cells to plasma cells, can be found in the TME.

  • The abundance, functional state and distribution of B cells within the TME are all highly dependent on the presence, location and maturity of tertiary lymphoid structures (TLS).

  • In immature TLS, B cells might acquire immunosuppressive activities, whereas those in mature TLS can undergo maturation, selection, amplification, somatic hypermutation and affinity maturation, and immunoglobulin class switching, leading to the production of plasma cells that secrete IgG or IgA.

  • Plasma cells generated in situ within intratumoural TLS can produce antibodies that target specific tumour-associated antigens; depending on their isotype and the immune contexture of the tumour, these antibodies can have anti-tumour or pro-tumour effects.

  • Intratumoural B cells and TLS are potential biomarkers of patient prognosis and response to immunotherapies; novel transcriptomic and imaging technologies will enable the correlations of particular B cell subsets with clinical outcomes to be better defined.

  • The development of interventions to induce intratumoural TLS, which facilitate B cell maturation towards antibody-producing plasma cells, as well as the characterization of anti-tumour antibodies generated in patients who respond to immunotherapy, will open promising therapeutic avenues.

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Fig. 1: B cell subtypes in cancer.
Fig. 2: Spatial organization of T cells and B cells the TME.
Fig. 3: Roles of B cells and TLS in cancer.
Fig. 4: Induction of intratumoural TLS in mouse models and patients with cancer.

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Acknowledgements

The authors thank A. Bougoüin and G. Pupier for their help in preparing Fig. 2 and C.-A. Reynaud for her help in defining the markers of B cell subsets. The work of the authors is supported by INSERM, Sorbonne Université, Université Paris Cité, La Ligue contre le Cancer (W.H.F.), the CARPEM (Cancer Research for Personalized Medicine) programme of the Sites Integrés de Recherche sur le Cancer (SIRIC) (C.S.-F.), LabeX Immunooncology (C.S.-F.), the Association pour la recherche en thérapeutiques innovantes en cancérologie (ARTIC; BioniKK contract (R17169DD) (C.S.-F.), the Fondation pour la recherche sur le cancer (ARC SIGN’IT) (A.I. and W.H.F.), the Institut du cancer (INCa; P-RTK 20-106) (A.I. and W.H.F.), the Cancéropole Ile de France (R18105DD INCA PL Bio) (C.M.S.), and the Recherche Hospitalo-Universitaire en santé (RHU) CONDOR programme (A.I. and W.H.F.).

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  1. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, Equipe inflammation, complément et cancer, Paris, France

    Wolf H. Fridman, Maxime Meylan, Cheng-Ming Sun & Catherine Sautès-Fridman

  2. Equipe labellisée Ligue contre le Cancer, Paris, France

    Wolf H. Fridman, Maxime Meylan, Cheng-Ming Sun & Catherine Sautès-Fridman

  3. MRC Centre for Reproductive Health, Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK

    Florent Petitprez

  4. Faculty of Medicine, University of Bordeaux, Bordeaux, France

    Antoine Italiano

  5. Department of Medicine, Institute Bergonié, Bordeaux, France

    Antoine Italiano

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All authors contributed equally to researching data for the article, discussions of content and writing the manuscript. W.H.F., M.M. and C.S.-F. reviewed/edited the manuscript before submission

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Fridman, W.H., Meylan, M., Petitprez, F. et al. B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome. Nat Rev Clin Oncol 19, 441–457 (2022). https://doi.org/10.1038/s41571-022-00619-z

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