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Humoral immunity, inflammation and cancer Tan and Coussens 211

HI-associated cytokines as mediators of several HI and Th2-associated cytokines, such as

tumor development IL-10, stimulate angiogenesis, and are therefore pro-

Molecular mechanisms by which HI impacts cancer ]. Increased IL-10 expression in patients

tumorigenic [22

initiation, promotion and progression are almost certainly with gastric cancer correlates with tumor angiogenesis,

multifaceted (Figure 1). Cytokines derived from evolving attenuated CD8+ T cell infiltration, and poor prognosis

]. Although, the literature has implicated IL-6 in both

neoplastic cells, activated resident stromal cells or infil- [22

Th1- and Th2-type responses, in several chronic inflam-

trating immune cells can regulate tumor growth by affect- matory diseases and various types of cancers, IL-6 is

ing angiogenesis, cell survival, death or differentiation. better known to direct Th2-type responses and play a

CMI and Th1-associated cytokines, such as IFN-g, tend central role as a differentiation and growth factor of

to exhibit anti-angiogenic bioactivities [21], whereas

Figure 1

Model for role of humoral immunity during inflammation-associated cancer development. Pre-malignant and malignant tissues are associated with

suppressed Th1 responses (i.e. IL-1 and IFNg) in combination with enhanced Th2 responses (i.e. IL-4, -6, -10 and -13). The latter leads to

activation of B cells that can inhibit Th1 anti-tumor immunity. Conversely, B cell activation also leads to immune complex (Ig:IC) accumulation in

serum and tissue interstitia that subsequently initiates pro-inflammatory activities and recruitment of innate immune cells (e.g. macrophages,

neutrophils and mast cells), possibly via C5aR and FcgRs, leading to chronic tumor-promoting inflammatory responses. C5a, generated through

classical/alternative, thrombin and/or cellular C3-independent pathways, induces chemotaxis of innate immune cells and modulates their function

via regulation of activating versus inhibitory FcgRs.

www.sciencedirect.com Current Opinion in Immunology 2007, 19:209–216

212 Tumour immunology

neoplastic epithelial cells [23,24]. IL-13 promotes survival ]. Adoptive transfer

lymphocyte (CTL) responses [29

and/or growth of selective tumor types through direct of B lymphocytes, but not serum, from wild-type mice

action on neoplastic cells, in addition to suppressing to B cell-deficient mice restored tumor growth accom-

CMI [25]. IL-23, a cytokine produced by dendritic cells panied by reduced Th1 cytokines and CTL response,

].

and macrophages following bacterial exposure and Toll- suggesting antibody-independent mechanisms [29

Together, these experimental findings support the con-

like receptor engagement, is also found highly expressed in cept that B cells limit anti-tumor immunity by inhibiting

various types of human carcinomas compared with adja- Th1 and CTL responses while simultaneously bolstering

cent normal tissue, indicating a potential important role in Th2-effector cell pro-tumor functions.

tumor development [26]. In a mouse model of chemical

carcinogenesis, absence of IL-23 resulted in a significant Do immunoglobulins play a functional role in

reduction in local inflammatory responses in the tumor solid tumor development?

microenvironment that paralleled an increase in cytotoxic Cancer patients often develop antibodies to tumor-associ-

T-cell infiltration, together resulting in resistance to car- ated antigens — evidence exists to support this for c-myc,

cinogenesis [26]. Thus, whereas IL-23 is not generally HER-2/neu and p53 [30]. However, production of these

considered as a Th2 cytokine, in this context, it is exerting antibodies does not confer protection, but, paradoxically,

Th2-like cytokine bioactivities by promoting inflamma- correlates with poor prognosis and decreased survival for

tory responses and inhibiting cytotoxic T cell responses. several human cancer types [31]. Anti-tumor antibodies

The degree to which effectiveness of IL-23 neutralization are thought to enhance tumor growth by promoting pro-

will translate to other mouse models of de novo carciogen- tumor immune responses and in general protecting tumor

esis and/or human cancer development is yet to be defined. cells from CTL-mediated killing [32]. Increased levels of

immunoglobulins (Ig) in neoplastic microenvironments

Thus, Th1- and Th2-associated cytokines act antagonisti- also result in accumulation of immune complexes (ICs)

cally in different tumor microenvironments, while in gen- that engender tumor-promoting inflammatory responses

eral a cytokine profile skewed toward Th2 responses [1,33]. Ig-IC formation is a significant feature of cancer

correlates with enhanced tumor promotion and pro- development: high circulating levels of ICs are associated

gression. It is unclear at present, however, if pro-tumor with increased tumor burden and poor prognosis in

bioactivities of Th2-associated cytokines are limited solely patients with breast, genitourinary, and head and neck

to their direct abilities to enhance pro-tumor pathways malignancies [34–36], and Ig deposition in neoplastic

(inflammation or angiogenesis), or more in their ability to stroma has been reported in pre-malignant and malignant

suppress CMI responses, or a combination of both. human breast and prostate tissues [1]. McDonald and

B-lymphocytes inhibit Th1 anti-tumor colleagues [37] recently reported that deposition of extra-

immunity vasated Ig in tumor stroma is due to enhanced leakiness of

As the central component of HI, B-lymphocytes function tumor blood vessels. Using a mouse model of islet cell

in antibody production, antigen presentation and carcinogenesis, non-specific and epitope-specific anti-

secretion of pro-inflammatory cytokines. In the context bodies (directed against extracellular matrix antigens)

of cancer development, in addition to altering local were infused into tumor-bearing animals and both were

and circulating profiles of cytokines, B cells also inhibit found to preferentially localize adjacent to leaky tumor

Th1-mediated anti-tumor immune responses. blood vessels in tumor stroma [37], thus implying that Ig-

IC depositions in neoplastic tissues is a general phenom-

In a syngeneic mouse mammary xenograft model, partial enon associated with cancer development and not necess-

B cell depletion resulted in significantly reduced tumor arily a directed process towards specific antigens, even

burden [20]. In experimental mouse models of lung when specific antigens are present.

adenocarcinoma, B cell deficiency significantly enhanced

therapeutic efficacy of combinatorial chemotherapy and In addition to forming immune complexes, IgG has also

IL-15, a Th-1 cytokine with IL-2-like anti-tumor bioac- been identified in complex with latent transforming

tivities [27]. In a mouse model of melanoma, B cell growth factor (TGF)-b [38]. Such complexes were pro-

deficiency provided a therapeutic advantage to a mela- posed to diminish directed primary CTL responses but

noma vaccine where enhanced tumor protection in the underlying mechanisms were not fully resolved. TGFb is

absence of B cells was associated with an increased a potent regulator of CTL function where it inhibits

magnitude and longevity of specific cellular immune secretion of cytolytic factors [39]. Kim and colleagues

] recently reported that genetic deficiency of key

response provoked by vaccination [28]. Moreover, Shah [40

] have reported that B-cell-deficient components of the TGF-b intracellular signaling cascade

and colleagues [29 + T cells significantly influenced

mice exhibit resistance to several histologically diverse (e.g. Smad4) in CD4

initiation, promotion and progression of epithelial cancer.

primary syngeneic tumors. Increased tumor resistance in Mice harboring homozygous null deletions in the Smad4

B-cell-deficient mice was found to be associated with + T cells spontaneously

gene preferentially in CD4

enhanced anti-tumor Th1 cytokines and cytolytic T

Current Opinion in Immunology 2007, 19:209–216 www.sciencedirect.com

Humoral immunity, inflammation and cancer Tan and Coussens 213

develop epithelial cancers in the gastrointestinal tract that are not only essential for resolving acute tissue damage

where prominent plasma cell hyperplasia was evident but also essential for promoting tumor development in

adjacent to developing duodenal polyps. Mice harboring initiated tissues.

germline mutations in Smad4 did not exhibit any of these

FcgR and C5a are key regulators of

]. Smad4-deficient T cells

same characteristics [40 IC-mediated inflammation

become skewed in their cytokine profile and prominently Inflammatory responses to ICs have been extensively

express several Th2-type cytokines including IL-4, -5, -6 studied in transgenic mouse models of various auto-

and -13. These pro-tumor mediators also enhance plasma immune diseases [47]. Mechanisms by which ICs initiate

cell differentiation, thus demonstrating that altering local inflammation are still not fully understood; however,

balances of important cytokine pathways, by differential receptors for the Fc portion of IgG (FcgRs, especially

regulation of either HI or CMI, profoundly influences FcgRIII) and complement factors (particularly C5a ana-

malignant risk and argues that perturbing these balances phylatoxin) are recognized as co-dominant effectors in the

to favor anti-tumor immunity represents a powerful anti- process [47]. Considering the fact that tissues damaged by

cancer approach. autoimmune dysfunction and by cancer have similar

ICs have long been suspected as initiators of inflamma- characteristics (e.g. chronic innate immune cell infiltra-

tory cascades associated with tissue destruction in auto- tion, tissue remodeling, angiogenesis, altered cell survival

immune diseases but underlying molecular mechanisms pathways) [48], it seems probable that similar IC effector

have been elusive [41]. Recent investigations of these pathways are involved in pathogenesis of both diseases.

mechanisms using an experimental mouse model of air-

way remodeling following Mycoplasma pulmonis infection Expressed on most leucocytes, FcgRs are classified into

have demonstrated that peripheral B cell responses and four groups (FcgRI/CD64, FcgRII/CD32, FcgRIII/

local Ig-IC deposition are the critical triggers for recruit- CD16 and recently identified FcgRIV) according to their

ing innate leucocytes into infected airways, that then distinct affinities for IgG, cell distributions and functions.

activate pro-angiogenic and tissue remodeling pathways FcgRI and FcgRIII, predominantly FcgRIII, mediate

necessary for resolving infection [42]. We have reported immune cell activation via their FcR chain that contains

g

complimentary findings using a transgenic mouse model an intracellular tyrosine-based activating motif (ITAM).

]. Here, oncogenes

of squamous carcinogenesis [43,44 Activating signals mediated by ITAM trigger oxidative

from human papillomavirus type 16 (HPV16) are bursts, cytokine release and phagocytosis by macro-

expressed in skin keratinocytes under direction of a phages, antibody-dependent cell-mediated cytotoxicity

human keratin 14 (K14) promoter/enhancer and initiate (ADCC) by natural killer (NK) cells, and degranulation of

multi-stage development of squamous cell carcinomas mast cells [41]. In contrast, engagement of FcgRIIB that

,45]. In HPV16 trans-

(SCCs) in skin and cervix [43,44 instead contains immune tyrosine-based inhibitory motifs

genic mice, combined B- and T-lymphocyte-deficiency (ITIM) inhibits these same inflammatory responses [41].

eliminated IC deposition in premalignant skin and atte- These two opposing regulatory pathways coexist on

nuated innate immune cell infiltrations, resulting in innate immune cells and thus, in part, determine the

diminished tissue remodeling activity, failure to activate magnitude of IC-mediated inflammatory responses.

angiogenic vasculature, retention of terminal differen- Indeed, the ratio of activating to inhibitory FcgR is

tiation programs in skin keratinocytes and a 43% reduction low in ’normal’ homeostatic tissues, and by contrast is

]. Adoptive transfer of B-

in overall SCC incidence [44 highly increased in inflamed microenvironments [47].

lymphocytes or serum isolated from HPV16 mice (but not

from wild-type naı̈ve mice) into B- and T-lymphocyte- Receptors for the Fc portion of IgG, FcgRs play a central

deficient/HPV16 mice restored IC deposition, chronic role in regulating immune responses following interaction

innate immune cell infiltration in pre-malignant skin with ICs [41]. It was recently demonstrated that presence

]. These

and reinstated parameters for full malignancy [44 or absence of sialic acid at the terminus of the core glycan in

].

data indicate that B-lymphocyte-derived factors, possibly the Fc region of IgG regulates immune response [49

Ig, are essential for establishing chronic inflammatory Sialylation of the Fc region of IgG reduces binding affi-

nities towards FcgRs thereby inhibiting pro-inflammatory

pathways that potentiate cancer development. In support activities of IgG, whereas reduction of sialylation, upon

of this concept, anti-tumor antibodies are known to antigen challenge, switches the immune response pathway

enhance outgrowth and invasion of murine and human from anti-inflammatory to pro-inflammatory via differen-

tumor-cell xenografts through recruitment and activation ]. Regu-

tial engagement with FcgRs on effector cells [49

of granulocytes and macrophages [33], which are important latory functions of FcgRs have been studied using

sources of vascular endothelial growth factor (VEGF) [46] genetically engineered animal models. Mice deficient in

that possesses pro-angiogenic bioactivities. Thus, serum the FcR chain or activating type FcgRs are resistant to a

proteins (presumably antibodies) produced by B-lympho- g

wide range of IC-mediated hypersensitive reactions, such

cytes locally or peripherally, at least in some scenarios, are as vasculitis, glomerulonephritis and skin Arthus reaction

crucial factors that initiate chronic inflammatory programs,

www.sciencedirect.com Current Opinion in Immunology 2007, 19:209–216


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Corso di laurea: Corso di laurea magistrale in medicina e chirurgia (ordinamento U.E. - durata 6 anni) (CASERTA, NAPOLI)
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I contenuti di questa pagina costituiscono rielaborazioni personali del Publisher valeria0186 di informazioni apprese con la frequenza delle lezioni di Patologia e Fisiopatologia Generale e studio autonomo di eventuali libri di riferimento in preparazione dell'esame finale o della tesi. Non devono intendersi come materiale ufficiale dell'università Seconda Università di Napoli SUN - Unina2 o del prof Castoria Gabriella.

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