Review Article
B cells and their mediators as targets for therapy in solid tumors

https://doi.org/10.1016/j.yexcr.2013.03.005Get rights and content

Abstract

B cells have recently been appreciated as paracrine mediators of solid tumor development. Their ability to influence various hallmarks of cancer development, aside from antigen presentation, can be attributed to the diversity of soluble mediators they express, including cytokines and immunoglobulins, that can act directly and indirectly on the diversity of leukocyte subsets that infiltrate developing tumors, evolving neoplastic cells, as well as select T cell populations in secondary lymphoid organs and within tumor stroma. Herein, we review the literature supporting these interactions and discuss novel approaches to ameliorate protumoral B cell effects for anti-cancer therapy.

Introduction

B lymphocytes, appropriately named for their original discovery in the Bursa of Fabricius, develop and mature in bone marrow, but are activated in peripheral lymphoid tissues in response to antigen (Ag) exposure, similar to T lymphocytes. However, unlike T cells whose primary immunological role is to “help” programming of other leukocytes or to exert selective killing (cytotoxicity), stimulation of naïve B cells culminates in production of secreted versions of B cell receptors (BCR) in the form of immunoglobulins (Ig), commonly referred to as antibodies. In addition, B cells secrete a variety of cytokines, e.g., interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, granulocyte monocyte-colony stimulating factor (GM-CSF) and lymphotoxin (LT), etc., that in turn regulate diverse activities of other leukocytes and non-hematopoietic cells. Moreover, their cell surface expression of major histocompatibility complex class (MHC)-II enables secondary antigen presentation to helper T (TH) cells. In homeostatic tissues, these activities are critical for maintaining tissue/organ health, but in pathological disease processes such as autoimmunity and cancer development, these same activities are diverted [1], [2]. Reviewed herein are the experimental and clinical studies supporting the paradoxical activities of B cells and their products in fostering carcinogenesis, examination of the paracrine mechanisms involved, and a discussion of a potential role for inhibitory B cell therapies in the clinic as either monotherapy, or in combination with chemotherapy, for patients with B cell-regulated solid tumors.

Section snippets

B cell subtypes in health and disease

The developmental progression from hematopoietic progenitor to pro- to pre- to finally immature, antigenically naïve B cell occurs consistently and predictably in every B cell subset prior to their exit from the fetal liver or adult bone marrow (in mammals) and chemotaxis to the periphery (Fig. 1). This process is directed by recombination activating genes 1 and 2 (RAG-1/2), DNA recombinases expressed in T and B cells that mediate T cell and B cell receptor gene rearrangement, culminating in

B cell cooperation with complement factors

A notable, yet underappreciated role for B cells in tumor development is the proteolytic induction of complement proteins that partner with Igs to form circulating immune complexes (CICs), and subsequently signal through complement receptors that are variably expressed on all leukocytes [12]. Induction of the complement cascade occurs in blood plasma and tissue, and is coordinated by a series of proteolytic zymogens, triggered on the surface of a pathogen and during activation of diverse

Role of immunoglobulins in tumor-associated chronic inflammation

While little is known on the functional significance of circulating immune complexes (CICs; Igs in biochemical complex with complement proteins) in tumor development, the role of CICs in inflammatory and autoimmune diseases has been examined extensively. CIC deposition into tissue parenchyma is a consequence of leaky vasculature, in both tumor [19], [20], [21] and pathologic [22] angiogenesis. CIC (and Ig) deposition initiates multiple inflammatory cascades by mechanisms involving activation of

Tumorigenic roles for B cell-derived cytokines

The data above indicate that B cells potentiate solid tumor development by mechanisms involving humoral immunity; however, in other experimental tumor models, serum CIC/Ig fails to reinstate B cell-dependent tumor parameters thus implying a role for other B cell-derived mediators (Fig. 2). During prostate carcinogenesis, the wingless-type MMTV integration site family member 16B (WNT16B) is upregulated by nuclear factor of kappa light polypeptide gene enhancer (NF-κB) in B cells after DNA

B cells as inhibitors of TH1-mediated anti-tumor immunity

In addition to altering local and circulating levels of cytokines, a significant role for B cells as (indirect) promoters of tumorigenesis lies in their ability to inhibit TH1-mediated anti-tumor immunity (Fig. 3). Enhanced TH1 (IFN-γ producing TH cells) and Tc (cytotoxic CD8+ T cells) anti-tumor immunity in B cell deficient mice (IgM−/−) leads to rejection and/or slowed onset of multiple transplanted tumor grafts [39]. Accordingly, direct IgG ligation of FcγRI/III on macrophages inhibits IL-12

Perspectives and therapeutic opportunities

From a classical point of view, it would seem likely that B cells contribute to tumorigenesis by impairing the process, and in deed they may under some circumstances. That the vast majority of humans do not develop cancer could in part be attributed to B cells, and other leukocytes, performing their intended vocations as they do when maintaining homeostatic tissue/organ health. However, as scientists begin to evaluate the fundamental molecular and cellular mechanisms contributing to cancer

Acknowledgments

The authors thank members of the Coussens laboratory for critical discussions on content. AJG is supported by T32I078903-04. LMC acknowledges support from the NIH/NCI, a DOD BCRP Era of Hope Scholar Expansion Award, Susan B Komen Foundation, and the Breast Cancer Research Foundation.

References (51)

  • S.K. Biswas

    A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation)

    Blood

    (2006)
  • D. Hanahan et al.

    Accessories to the crime: functions of cells recruited to the tumor microenvironment

    Cancer Cell

    (2012)
  • M. Aklilu

    Depletion of normal B cells with rituximab as an adjunct to IL-2 therapy for renal cell carcinoma and melanoma

    Ann. Oncol.

    (2004)
  • D.J. Dilillo et al.

    B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer

    Ann. N.Y. Acad. Sci.

    (2010)
  • J.K. Bubien et al.

    Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes

    J. Cell Biol.

    (1993)
  • J. Uchida

    Mouse CD20 expression and function

    Int. Immunol.

    (2004)
  • T.W. Kuijpers

    CD20 deficiency in humans results in impaired T cell-independent antibody responses

    J. Clin. Invest.

    (2010)
  • P. McLaughlin et al.

    Clinical status and optimal use of rituximab for B-cell lymphomas

    Oncology (Huntingt)

    (1998)
  • M.J. Leandro et al.

    Rheumatic diseases and malignancy—is there an association?

    Scand. J. Rheumatol.

    (2001)
  • S. Bernatsky et al.

    Malignancy and autoimmunity

    Curr. Opin. Rheumatol.

    (2006)
  • M.C. Carroll

    The complement system in regulation of adaptive immunity

    Nat. Immunol.

    (2004)
  • J. Pepys et al.

    Clinical and immunological responses to enzymes of Bacillus subtilis in factory workers and consumers

    Clin. Allergy

    (1973)
  • N. Shushakova

    C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease

    J. Clin. Invest.

    (2002)
  • J. Godau

    C5a initiates the inflammatory cascade in immune complex peritonitis

    J. Immunol.

    (2004)
  • F. Nimmerjahn et al.

    Analyzing antibody-Fc-receptor interactions

    Methods Mol. Biol.

    (2008)
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