Patologia e fisiopatologia generale - infiammazione e tumori prima parte

Humoral immunity, inflammation and cancer

1 1,2,3

Ting-Ting Tan and Lisa M Coussens tissue damage, has only recently been revealed as an

Clinical and experimental data now clearly indicate that chronic important regulator of cancer development [2,3]. By

inflammation significantly contributes to cancer development. contrast, tumor immunologists have long focused on

Emerging out of these studies is an appreciation that persistent anti-tumor activities of the adaptive immune system,

humoral immune responses exacerbate recruitment and and as such have investigated utility of anti-tumor immu-

activation of innate immune cells in neoplastic notherapeutics with which to combat neoplastic disease

microenvironments where they regulate tissue remodeling, [1]. When considering the adaptive immune system as a

pro-angiogenic and pro-survival pathways that together therapeutic tool, however, it is important to consider both

potentiate cancer development. Population-based studies humoral immunity (HI) and cell-mediated immunity

examining individuals with chronic inflammatory disorders (CMI).

have revealed that states of suppressed cellular immunity,

in combination with enhanced humoral immunity and

humoral immunity-associated cytokines, cooperate and This review focuses on the role of persistent humoral-

effectively suppress anti-tumor immune responses while mediated inflammatory responses associated with tumor

simultaneously enhancing angiogenesis and presumably development and examines the molecular pathways they

overall cancer risk in afflicted tissue. In addition, studies in activate that might differentially regulate cancer pro-

transgenic mouse models of de novo organ-specific cancer motion and/or progression.

development have revealed that inflammation mediated by Imbalances in humoral and cell-mediated

immunoglobulins and immune complexes might be functionally immunity are associated with cancer

significant parameters of tumor promotion and progression. development

These recent advances support the hypothesis that enhanced

states of local humoral and innate immune activation, in Pre-malignant and malignant tissues are known to be

combination with suppressed cellular immunity and failed associated with alterations in immune cell functions

cytotoxic T cell anti-tumor immunity, alter cancer risk and (Table 1). Such alterations include suppressed CMI,

therefore represent powerful targets for anti-cancer associated with failure to reject tumors, in combination

immunotherapeutics. with enhanced HI that can potentiate tumor promotion and

+ T-cell subsets (e.g. Th1

progression [4]. Distinctive CD4

Addresses

1 Department of Pathology, University of California, San Francisco 2340 or Th2 T helper cells) secrete unique repertoires of cyto-

Sutter St, San Francisco, CA 94143, USA kines that mediate their responses. Th1 cells produce

2 Cancer Research Institute, University of California, San Francisco 2340 interleukin (IL)-2 and interferon (IFN)-g for example,

Sutter St, San Francisco, CA 94143, USA and therefore direct CMI responses, whereas Th2 cells

3 Comprehensive Cancer Center, University of California, San Francisco produce IL-4 and IL-10, for example, and facilitate local

2340 Sutter St, San Francisco, CA 94143, USA HI responses. In peripheral blood of patients with blad-

Corresponding author: Coussens, Lisa M (coussens@cc.ucsf.edu) der and colorectal cancer, proportions of Th1 cells,

identified by intracellular production of IFNg or IL-2,

is markedly reduced, whereas proportions of Th2

Current Opinion in Immunology 2007, 19:209–216 cells producing IL-4, IL-6 and/or IL-10 is significantly

This review comes from a themed issue on elevated, as compared with proportions of Th1 and Th2

Tumour immunology in otherwise healthy patient populations [5,6]. A recent

Edited by Mark Smyth study investigating characteristics of leukocytic infiltra-

Available online 2nd February 2007 tions within colorectal cancers found that CD3+ T

lymphocyte densities within tumor biopsies, as opposed

0952-7915/$ – see front matter to peripheral blood, represented a better predictor of

2006 Elsevier Ltd. All rights reserved.

# patient survival than current histopathological staging

DOI 10.1016/j.coi.2007.01.001 ]. Moreover, in human cervical carcinomas,

methods [7

CD3+ tumor infiltrating T cells display enhanced Th2

cytokine profiles, specifically increased IL-4 and reduced

Introduction IFN-g production [8].

Early and persistent inflammatory-type responses in or

around developing neoplasms are thought to regulate many In keeping with these findings, alterations in immune cell

aspects of tumor development [1]. The innate immune status (suppressed CMI and enhanced HI) have also been

system, extensively studied in the context of autoimmune reported in chronic inflammatory diseases associated with

disease and wound healing following pathogen infection or ,12,13]. For

increased cancer risk (Table 1) [4,9,10,11

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

210 Tumour immunology

Table 1

Enhanced humoral immunity in pre-malignant and malignant diseases.

Disease state Reported alteration in immune status/function References

Malignant tissue

Bladder cancer Decreased number of Th1 cells and increased number of Th2 cells in peripheral blood [5]

Colorectal cancer Decreased number of Th1 cells and increased number of Th2 cells in peripheral blood and [6]

increased Th2 cytokines in serum

Cervical cancer Lymphocytes derived from human cervical cancer tissue consisted mainly of Th2/Tc2 [8]

phenotypes

Gastric cancer Decreased ratio of Th1 cell to Th2 cell in peripheral blood and increased IL-10 in serum [6,22 ]

Head and neck cancer High level of immune complexes correlates with increased tumor burden and poor prognosis [34–36]

Breast cancer

Genitourinary

Pre-malignant tissue

Ulcerative colitis B cell activation and markedly skewed local IgG response in intestines [4,9]

1

Asbestosis Increased immunoglobulin and immune-complex, and higher levels of IL-6 and IL-8 in the [4,10]

peripheral blood of patients with asbestosis

Barrett’s esophagus Replacement of Th1 effector cells with Th2 effector cells in inflamed tissue [11 ]

HCV-related cirrhosis Decreased number of Th1 cells and increased number of Th2 cells in peripheral blood [4,12]

Chronic obstructive airway disease T lymphocytes in bronchoalveolar lavage from patients with COPD displayed increased [4,13]

(COPD) intracellular expression of Th2 cytokines

example, intestinal B cell responses have been observed in infection has been observed in patients treated with

ulcerative colitis, a benign condition with a high risk for Rituximab for rheumatoid arthritis or non-Hodgkin’s

colorectal cancer development [4,9]. Decreased Th1/Th2 lymphoma [17], thus engendering support for systemi-

ratios in peripheral blood have been reported in Hepatitis cally manipulating humoral immune responses as a thera-

C virus-related liver cirrhosis, a liver disease closely associ- peutic approach.

ated with hepatocellular carcinoma [12]. In Barrett’s eso-

phagus, an intermediate step in the progression from reflux The mechanistic links between autoimmune diseases,

esophagitis to esophageal adenocarcinoma, infiltration of such as rheumatoid arthritis, Sjogren’s syndrome and

+ T cells) is

Th1 effector cells (macrophages and CD8 SLE, with non-Hodgkin’s lymphoma are undisputed;

largely replaced by Th2 effector cells (IgG producing however, the association of solid tumors with autoimmu-

plasma cells and mast cells) when reflux esophagitis pro- nity has not been well described [14]. Cohort studies have

]. Taken together, these

gresses to Barrett’s esophagus [11 found increased risk for lung cancer in rheumatoid arthri-

compelling clinical findings indicate that pronounced tis patients [14], and a modestly increased risk for all

HI may underlie increased risk for neoplastic progression cancers, particularly lung cancer and hepatobiliary can-

in tissues afflicted with chronic inflammatory disease cers, in SLE patients [14]. Clinical studies of patients

pathologies. with systemic sclerosis have also revealed increased risk

for lung cancer, non-melanoma skin cancers and breast

Autoimmune disorders caused by B cell hyperactivity are cancer [19]. Mechanisms contributing to these enhanced

also associated with cancer [14]. B cells are known to cancer risks are largely elusive; however, given pro-

initiate autoimmunity through several mechanistic path- nounced humoral immune responses in afflicted tissues,

ways including enhanced production of autoantibodies, it is intriguing to speculate that autoantibody–antigen

immune complexes, dendritic and T cell activation and complex formation and deposition in neoplastic micro-

cytokine production [15]. The pathogenic role for B cells environments might contribute. Support for this hypoth-

in autoimmune disease is supported by clinical success of esis comes from a limited clinical study where advanced

B cell depletion therapy using a chimeric monoclonal colon cancer patients were treated with Rituximab. In

antibody (MoAb) specific for human CD20 (e.g. Ritux- these individuals, numbers of CD21-hyperpositive

imab) in patients with rheumatoid arthritis, systemic lymphocytes were reduced in parallel with a 50%

lupus erythematosus (SLE) and others [16,17]. Rituximab reduction in tumor burden with no ill-effects as a result

has also found clinical efficacy in adult acute lympho- of the therapy [20]. Taken together, the clinical data

blastic leukaemia (ALL) — monotherapy in patients with indicate a role for enhanced HI and inflammation, in

relapsed ALL has achieved modest success, but greater combination with suppressed CMI, in the pathogenesis

effects have been found in combination with chemother- of several human cancer types — mechanistic investi-

apy and in treatment for minimal residual disease [18]. gation of the molecular and cellular pathways mediating

Although Rituximab effectively deletes the vast majority enhanced cancer risk will surely identify new therapeutic

of circulating B cells, no increased susceptibility to targets with which to combat neoplastic disease.

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

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). Cyt