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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


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, Current Opinion in Immunology 2007, 19:209–216

214 Tumour immunology

[41]. Conversely, mice deficient in FcgRIIB exhibit initiate significant pro-tumor effects on developing neo-

enhanced IC-mediated inflammatory responses [41]. plasms. We propose that bolstering anti-tumor cell-

Although these elegant genetic studies demonstrate func- mediated immune responses, in combination with neutra-

tional importance of FcgRs in IC-mediated inflammation lizing potent pro-tumor humoral immune responses with

and autoimmune diseases, little is known about their role in efficacious immuno-therapeutics, would effectively direct

tumor development. tumor suppression while establishing an immune environ-

ment favoring therapeutic responses to conventional anti-

Complement activation is a central event during innate tumor modalities. Certainly, further studies are needed to

immune defence following pathogenic tissue assault. determine the universality of this approach and specifically

Three different pathways of complement activation have which types of human cancers would be amenable to such

been identified, namely classical, alternative and lectin therapy. Nonetheless, a dedicated attempt to reveal the

pathways. Foreign antigens and ICs activate complement molecular and cellular mechanisms linking HI, inflam-

cascades resulting in formation of lytic membrane attack mation and cancer will also provide important insights into

complexes and formation and liberation of anaphylatox- viable therapeutic targets for anti-cancer therapy.

ins; for example, C3a and C5a, potent pro-inflammatory Acknowledgements

factors that induce recruitment and activation of leuko- We acknowledge all the scientists who made contributions to the areas of

cytes. Deposition of complement proteins is a common research reviewed here that were not cited due to space constraints. The

occurrence at sites of inflammation. Studies utilizing authors were supported by grants from the National Institutes of Health

complement depleted mice and C3- or C5-deficient mice (CA72006, CA94168, CA098075), Sandler Program in Basic Sciences,

National Technology Center for Networks and Pathways (U54 RR020843)

have identified their crucial roles in regulating disease and a Department of Defense Era of Hope Scholar Award (BC051640).

pathogenesis [50,51]. We previously reported abundant

deposition of C3 in neoplastic skin of HPV16 mice; but References and recommended reading

found that C3-deficiency was without functional con- Papers of particular interest, published within the annual period of

review, have been highlighted as:

sequence, indicating that if Ig-ICs enhance premalignant

progression, they most likely contribute via regulation of of special interest

of outstanding interest

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Corso di laurea: Corso di laurea magistrale in medicina e chirurgia (ordinamento U.E. - durata 6 anni) (CASERTA, NAPOLI)

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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