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Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities

Abstract

Although immunotherapy research to date has focused largely on T cells, there is mounting evidence that tumour-infiltrating B cells and plasma cells (collectively referred to as tumour-infiltrating B lymphocytes (TIL-Bs)) have a crucial, synergistic role in tumour control. In many cancers, TIL-Bs have demonstrated strong predictive and prognostic significance in the context of both standard treatments and immune checkpoint blockade, offering the prospect of new therapeutic opportunities that leverage their unique immunological properties. Drawing insights from autoimmunity, we review the molecular phenotypes, architectural contexts, antigen specificities, effector mechanisms and regulatory pathways relevant to TIL-Bs in human cancer. Although the field is young, the emerging picture is that TIL-Bs promote antitumour immunity through their unique mode of antigen presentation to T cells; their role in assembling and perpetuating immunologically ‘hot’ tumour microenvironments involving T cells, myeloid cells and natural killer cells; and their potential to combat immune editing and tumour heterogeneity through the easing of self-tolerance mechanisms. We end by discussing the most promising approaches to enhance TIL-B responses in concert with other immune cell subsets to extend the reach, potency and durability of cancer immunotherapy.

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Fig. 1: B cells in health and malignancy.
Fig. 2: B cell differentiation and tolerance.
Fig. 3: TIL-B neighbourhoods.
Fig. 4: Model for intramolecular epitope spreading from neo-epitopes to self-epitopes in cancer.
Fig. 5: TIL-B effector mechanisms.

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Acknowledgements

The authors thank K. Singh, T. Rastogi and K. Milne for technical assistance with multicolour immunofluorescence staining and image processing for Fig. 3. C.M.L. is supported by postdoctoral fellowships from Canadian Institutes of Health Research (CIHR) (Banting postdoctoral fellowships programme, 429161) and Michael Smith Foundation for Health Research (MSFHR) (RT-2020-0630). A.C.B. is supported by a Doctoral Award from CIHR (Frederick Banting and Charles Best Canada Graduate Scholarship, FBD — 177882). M.G. and D.P.H. were supported by funds from the National Institutes of Health (NIH P30 CA014195), 2021 Metavivor Early Career Investigator Award, and the San Diego Padres Pedal the Cause C3 Collaborative Translational Cancer Pilot Project Award.

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All authors researched literature, contributed to discussions of the content of the article and edited or reviewed the manuscript before submission. C.M.L. and B.H.N. wrote the final version of the manuscript.

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Correspondence to Brad H. Nelson.

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Glossary

Exhausted or dysfunctional CD8+ and CD4+ TILs

(Exhausted or dysfunctional CD8+ and CD4+ tumour-infiltrating lymphocytes). Adysfunctional T cell state triggered by chronic antigen exposure and characterized by poor effector functions (for example, cytokine production), sustained expression of inhibitory receptors (for example, PD-1, cytotoxic T lymphocyte-associated protein 4 (CTLA4)) and widespread transcriptomic changes. Exhausted T cells can be placed on a dysfunction continuum (pre-dysfunctional, early dysfunctional and late dysfunctional) based on their clonality (intermediate to high) and their expression of C–X–C motif chemokine ligand 13 (CXCL13) and inhibitory receptors (intermediate to high).

Clonal redemption

A process by which moderately self-reactive anergic B cells are recruited to the germinal centre, where somatic hypermutation gives them the opportunity to mutate away from self-reactivity.

CD40

A molecule central to B cell activation; upon binding to its ligand expressed by activated T cells, CD40 promotes B cell survival and proliferation, germinal centre formation and development of memory B cells and long-lived plasma cells (PCs).

Somatic hypermutation

A process by which antigen-activated B cells acquire somatic mutations in their B cell receptor (BCR) sequence, thereby leading to receptor diversification.

Affinity maturation

A process by which the diverse repertoire of B cell receptors (BCRs) generated by somatic hypermutation is screened to select clones with the highest affinity for their cognate antigen.

Secondary lymphoid organs

Peripheral organs, such as the spleen and lymph nodes, that provide the optimal environment to generate and quench adaptive immune responses.

Antibody-dependent cellular cytotoxicity

(ADCC). A process by which Fc receptor-expressing effector cells, such as natural killer cells and macrophages, recognize antibody-coated cells and orchestrate their destruction through the release of cytotoxic granules.

Antibody-dependent cellular phagocytosis

(ADCP). A process by which Fc receptor-expressing phagocytes, typically macrophages, recognize antibody-coated cells and destroy them by engulfment.

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Laumont, C.M., Banville, A.C., Gilardi, M. et al. Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities. Nat Rev Cancer 22, 414–430 (2022). https://doi.org/10.1038/s41568-022-00466-1

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