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  • Review Article
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Targeting B cell receptor signalling in cancer: preclinical and clinical advances

Nature Reviews Cancer volume 18, pages 148–167 (2018)Cite this article

Subjects

Key Points

  • B cell receptor (BCR) signalling is indispensable for normal B cell development and adaptive immunity. In some B cell leukaemias and lymphomas, malignant B cells utilize BCR signalling for growth and survival.

  • The mechanism of activation of BCR signalling includes continuous BCR stimulation by microbial antigens and/or autoantigens that are present in the tissue microenvironment, oncogenic mutations within the BCR complex or downstream signalling components and ligand-independent tonic BCR signalling.

  • Bruton tyrosine kinase (BTK) inhibitors and/or PI3Kδ selective inhibitors are effective against chronic lymphocytic leukaemia (CLL), mantle cell lymphoma, follicular lymphoma, Waldenstrom macroglobulinaemia (WM) and other selective B cell malignancies. In CLL and WM, BTK inhibitors are increasingly replacing chemotherapy.

  • BTK and PI3Kδ inhibitors cause redistribution of malignant B cells from tissue sites into the peripheral blood, especially in patients with CLL. How much this redistribution, resulting in a form of programmed cell death (anoikis) as a consequence of detachment of the malignant cells from their supportive tissue microenvironment, contributes to the efficacy of these agents remains unclear. The involvement of BTK, PI3Kδ and other BCR-related kinases such as spleen tyrosine kinase (SYK) in the signalling and function of homing receptors (chemokine receptors and integrins) appears to be the molecular basis for this B cell redistribution.

  • BTK and PI3Kδ are also expressed in non-malignant cells in the microenvironment, such as T cells and monocytes and macrophages. The effects of BTK and PI3Kδ inhibitors extend to these cell lineages, which may contribute to antitumour effects but can give rise to side effects. In addition, ibrutinib, the most widely used BTK inhibitor, also targets inducible T cell kinase (ITK), a related kinase that promotes T helper 2 (TH 2) cell differentiation.

  • B cells and macrophages are part of a tumour-supportive microenvironment in solid tumours, including pancreatic cancer. Targeting B cell and/or macrophage function yields antitumour effects in preclinical models, and this strategy is being investigated in ongoing clinical trials.

Abstract

B cell receptor (BCR) signalling is crucial for normal B cell development and adaptive immunity. BCR signalling also supports the survival and growth of malignant B cells in patients with B cell leukaemias or lymphomas. The mechanism of BCR pathway activation in these diseases includes continuous BCR stimulation by microbial antigens or autoantigens present in the tissue microenvironment, activating mutations within the BCR complex or downstream signalling components and ligand-independent tonic BCR signalling. The most established agents targeting BCR signalling are Bruton tyrosine kinase (BTK) inhibitors and PI3K isoform-specific inhibitors, and their introduction into the clinic is rapidly changing how B cell malignancies are treated. B cells and BCR-related kinases, such as BTK, also play a role in the microenvironment of solid tumours, such as squamous cell carcinoma and pancreatic cancer, and therefore targeting B cells or BCR-related kinases may have anticancer activity beyond B cell malignancies.

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Figure 1: B cell receptor signalling in B cell development and maturation.
Figure 2: The B cell receptor signalling pathway.
Figure 3: Normal and malignant B cell proliferation in secondary lymphoid organs.
Figure 4: Antigen-dependent and oncogenic B cell receptor signalling in B cell malignancies.
Figure 5: The role of tumour-infiltrating B cells in pancreatic ductal adenocarcinoma.

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Acknowledgements

J.A.B. is supported by a Leukaemia & Lymphoma Society Scholar Award in Clinical Research, MD Anderson's Moon Shot Program in CLL, the CLL Global Research Foundation, and in part by the MD Anderson Cancer Center Support Grant CA016672. A.W. is supported by the intramural research programme of the National Heart, Lung and Blood Institute (NHLBI) of the US National Institutes of Health (NIH).

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA

    Jan A. Burger

  2. Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Adrian Wiestner

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  1. Jan A. Burger
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Contributions

J.A.B. and A.W. contributed equally to writing the article and to the review and editing of the manuscript before submission.

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Correspondence to Jan A. Burger.

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Competing interests

J.A.B. received research funding from Pharmacyclics and Gilead. A.W. received research support from Pharmacyclics and Acerta Pharma.

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Glossary

Chronic lymphocytic leukaemia

(CLL). A common malignancy of CD5+ B cells that is characterized by an accumulation of small, mature-appearing lymphocytes in the blood, bone marrow and lymphoid tissues that are highly dependent on their microenvironment and B cell receptor signalling for survival and growth.

Mantle cell lymphoma

(MCL). A rare, aggressive CD5+ B cell lymphoma involving the lymph nodes, spleen, blood and bone marrow; genetically characterized by the translocation t(11;14)(q13;q32) and overexpression of cyclin D1 (CCND1).

Pro-B cells

Earliest-stage B cells, characterized by ongoing heavy chain diversity (D)–joining (J) rearrangement.

Pre-B cells

Differentiate from pro-B cells and express the pre-B cell receptor composed of μ heavy chain paired with the surrogate light chain. These cells activate light chain rearrangement and deficiency in PI3Kδ or BTK block maturation of the cells at this stage.

Agammaglobulinaemia

A group of primary immunodeficiencies characterized by lack of functional B cells and antibodies due to mutations in genes encoding components of the pre-B cell receptor or B cell receptor or their respective signalling pathways.

Secondary lymphoid organs

(SLOs). Sites (lymph nodes, spleen, Peyers patches and mucosa-associated lymphoid tissue) where mature naive lymphocytes are activated by antigen and initiate adaptive immune responses.

Germinal centres

Microanatomical site within secondary lymphoid organs where B cells expand in response to antigenic stimulation, undergo affinity maturation of the B cell receptor through somatic hypermutation and further mature to become memory B cells or plasma cells.

Activation-induced cytidine deaminase

(AID). Gene editing enzyme expressed primarily in germinal centre B cells of secondary lymphoid organs. AID introduces point mutations into the variable and switch regions of immunoglobulin genes during the processes of somatic hypermutation and class switch recombination.

Somatic hypermutation

A process that enables B cells to mutate the immunoglobulin genes in the hypervariable regions (corresponding to the complementarity-determining regions) and in the framework region of the variable chain genes, involving activation-induced cytidine deaminase (AID). This leads to diversification of the B cell receptor repertoire in antigen-activated B cells.

Class switch recombination

A process by which B cells rearrange the constant region genes in the immunoglobulin heavy chain locus to switch from expressing one class of immunoglobulin, such as IgM, to another, such as IgG or IgA, without affecting antigen specificity.

Marginal zone B cells

Innate-like B cells confined to the marginal zone of the spleen, the inner wall of the subcapsular sinus of lymph nodes, the epithelium of tonsillar crypts and the subepithelial area of mucosa-associated lymphoid tissues that can recognize conserved microbial antigens.

Humoral immunity

Describes parts of the immune system that are found in extracellular fluids, such as antibodies, complement proteins and antimicrobial peptides.

T helper cells

(TH cells). T cells that support immune reactions, in particular in the adaptive immune system, through secretion of cytokines and interactions with other immune cells.

Autoantigens

A normal body constituent that is recognized by the immune system as a foreign antigen. Reactivity to autoantigens is common in autoimmune diseases.

Diffuse large B cell lymphoma

(DLBCL). The most common B cell non-Hodgkin lymphoma; an aggressive B cell lymphoma with heterogeneous clinical presentations and high molecular diversity. The activated B cell-like (ABC-DLBCL) subtype is characterized by constitutive activation of the nuclear factor-κB (NF-κB) pathway that is commonly associated with chronic active B cell receptor signalling.

Centroblasts

Large activated B cells that are proliferating and undergoing somatic hypermutation in the dark zone of the germinal centre.

Centrocytes

B cells arising from centroblasts that have stopped proliferating and have migrated to the light zone of the germinal centre, where they can undergo selection, class switch recombination and differentiation.

Antibody affinity maturation

Darwinian process in germinal centres that results in the stepwise selection and expansion of B cells that produce high-affinity antibodies. It is based on alternation between somatic hypermutation of immunoglobulin genes and selection and clonal expansion of B cells that have acquired affinity-enhancing mutations.

Follicular lymphoma

(FL). The most common indolent non-Hodgkin lymphoma, derived from germinal centre B cells. Malignant FL centroblasts and centrocytes carry the hallmark t(14;18)(q32;q21) translocation that causes BCL-2 dysregulation and inactivating mixed-lineage leukaemia 2 (MLL2; also known as KMT2D) mutations.

Anergy

A state of cellular unresponsiveness to further stimulation that can result from repetitive or hyperactive stimulation.

Waldenstrom macroglobulinaemia

(WM). A plasmacytic lymphoma of mature B cells characterized by the secretion of clonal immunoglobulin M (IgM) that can damage organs and nerves, leading to disease-related symptoms.

Idiotype

The variable regions in an antibody, B cell receptor or T cell receptor that determine the antigen specificity.

Burkitt lymphoma

(BL). An aggressive B cell malignancy derived from rapidly proliferating germinal centre centroblasts, characterized by overexpression of MYC and a dependency on tonic B cell receptor-related signalling with PI3K pathway activation.

Redistribution lymphocytosis

Mobilization of tissue-resident or malignant lymphocytes into the peripheral blood. Commonly seen in patients with chronic lymphocytic leukaemia (CLL) during the first months of treatment with Bruton tyrosine kinase (BTK) inhibitors, PI3Kδ inhibitors or glucocorticoids.

Tumour lysis syndrome

Metabolic and electrolyte abnormalities arising when large numbers of tumour cells are killed at the same time; a common complication of cancer therapy.

Small lymphocytic lymphoma

(SLL). A B cell lymphoproliferative disease that has the tissue morphology and immune phenotype of chronic lymphocytic leukaemia (CLL) but is not leukaemic (with less than 5,000 clonal B cells per microlitre of blood).

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Burger, J., Wiestner, A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer 18, 148–167 (2018). https://doi.org/10.1038/nrc.2017.121

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