Patologia e fisiopatologia generale - infiammazione e tumori prima parte

Humoral immunity, inflammation and cancer

1 1,2,3Ting-Ting Tan and Lisa M Coussens

Clinical and experimental data now clearly indicate that chronic inflammation significantly contributes to cancer development. Emerging out of these studies is an appreciation that persistent humoral immune responses exacerbate recruitment and activation of innate immune cells in neoplastic microenvironments where they regulate tissue remodeling, pro-angiogenic and pro-survival pathways that together potentiate cancer development. Population-based studies examining individuals with chronic inflammatory disorders have revealed that states of suppressed cellular immunity, in combination with enhanced humoral immunity and humoral immunity-associated cytokines, cooperate and effectively suppress anti-tumor immune responses while simultaneously enhancing angiogenesis and presumably overall cancer risk in afflicted tissue. In addition, studies in transgenic mouse models of de novo organ-specific cancer development have revealed that inflammation mediated by immunoglobulins and immune complexes might be functionally significant parameters of tumor promotion and progression. These recent advances support the hypothesis that enhanced states of local humoral and innate immune activation, in combination with suppressed cellular immunity and failed cytotoxic T cell anti-tumor immunity, alter cancer risk and therefore represent powerful targets for anti-cancer immunotherapeutics.

Addresses

1 Department of Pathology, University of California, San Francisco 2340 Sutter St, San Francisco, CA 94143, USA

2 Cancer Research Institute, University of California, San Francisco 2340 Sutter St, San Francisco, CA 94143, USA

3 Comprehensive Cancer Center, University of California, San Francisco 2340 Sutter St, San Francisco, CA 94143, USA

Corresponding author: Coussens, Lisa M (coussens@cc.ucsf.edu)

Current Opinion in Immunology 2007, 19:209–216

This review comes from a themed issue on Tumour immunology

Edited by Mark Smyth

Available online 2nd February 2007

0952-7915/$ – see front matter

2006 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.coi.2007.01.001

Introduction

Early and persistent inflammatory-type responses in or around developing neoplasms are thought to regulate many aspects of tumor development [1]. The innate immune system, extensively studied in the context of autoimmune disease and wound healing following pathogen infection or tissue damage, has only recently been revealed as an important regulator of cancer development [2,3]. By contrast, tumor immunologists have long focused on anti-tumor activities of the adaptive immune system, and as such have investigated utility of anti-tumor immunotherapeutics with which to combat neoplastic disease [1]. When considering the adaptive immune system as a therapeutic tool, however, it is important to consider both humoral immunity (HI) and cell-mediated immunity (CMI).

This review focuses on the role of persistent humoral-mediated inflammatory responses associated with tumor development and examines the molecular pathways they activate that might differentially regulate cancer promotion and/or progression.

Imbalances in humoral and cell-mediated immunity are associated with cancer development

Pre-malignant and malignant tissues are known to be associated with alterations in immune cell functions (Table 1). Such alterations include suppressed CMI, associated with failure to reject tumors, in combination with enhanced HI that can potentiate tumor promotion and progression [4]. Distinctive CD4+ T-cell subsets (e.g. Th1 or Th2 T helper cells) secrete unique repertoires of cytokines that mediate their responses. Th1 cells produce interleukin (IL)-2 and interferon (IFN)-g for example, and therefore direct CMI responses, whereas Th2 cells produce IL-4 and IL-10, for example, and facilitate local HI responses. In peripheral blood of patients with bladder and colorectal cancer, proportions of Th1 cells, identified by intracellular production of IFNg or IL-2, is markedly reduced, whereas proportions of Th2 cells producing IL-4, IL-6 and/or IL-10 is significantly elevated, as compared with proportions of Th1 and Th2 in otherwise healthy patient populations [5,6]. A recent study investigating characteristics of leukocytic infiltrations within colorectal cancers found that CD3+ T lymphocyte densities within tumor biopsies, as opposed to peripheral blood, represented a better predictor of patient survival than current histopathological staging methods [7]. Moreover, in human cervical carcinomas, CD3+ tumor infiltrating T cells display enhanced Th2 cytokine profiles, specifically increased IL-4 and reduced IFN-g production [8].

In keeping with these findings, alterations in immune cell status (suppressed CMI and enhanced HI) have also been reported in chronic inflammatory diseases associated with increased cancer risk (Table 1) [4,9,10,11,12,13]. For example, intestinal B cell responses have been observed in ulcerative colitis, a benign condition with a high risk for colorectal cancer development [4,9]. Decreased Th1/Th2 ratios in peripheral blood have been reported in Hepatitis C virus-related liver cirrhosis, a liver disease closely associated with hepatocellular carcinoma [12]. In Barrett’s esophagus, an intermediate step in the progression from reflux esophagitis to esophageal adenocarcinoma, infiltration of Th1 effector cells (macrophages and CD8+ T cells) is largely replaced by Th2 effector cells (IgG producing plasma cells and mast cells) when reflux esophagitis progresses to Barrett’s esophagus [11]. Taken together, these compelling clinical findings indicate that pronounced HI may underlie increased risk for neoplastic progression in tissues afflicted with chronic inflammatory disease pathologies.

Autoimmune disorders caused by B cell hyperactivity are also associated with cancer [14]. B cells are known to initiate autoimmunity through several mechanistic pathways including enhanced production of autoantibodies, immune complexes, dendritic and T cell activation and cytokine production [15]. The pathogenic role for B cells in autoimmune disease is supported by clinical success of B cell depletion therapy using a chimeric monoclonal antibody (MoAb) specific for human CD20 (e.g. Rituximab) in patients with rheumatoid arthritis, systemic lupus erythematosus (SLE) and others [16,17]. Rituximab has also found clinical efficacy in adult acute lymphoblastic leukaemia (ALL) — monotherapy in patients with relapsed ALL has achieved modest success, but greater effects have been found in combination with chemotherapy and in treatment for minimal residual disease [18]. Although Rituximab effectively deletes the vast majority of circulating B cells, no increased susceptibility to infection has been observed in patients treated with Rituximab for rheumatoid arthritis or non-Hodgkin’s lymphoma [17], thus engendering support for systemically manipulating humoral immune responses as a therapeutic approach.

The mechanistic links between autoimmune diseases, such as rheumatoid arthritis, Sjogren’s syndrome and SLE, with non-Hodgkin’s lymphoma are undisputed; however, the association of solid tumors with autoimmunity has not been well described [14]. Cohort studies have found increased risk for lung cancer in rheumatoid arthritis patients [14], and a modestly increased risk for all cancers, particularly lung cancer and hepatobiliary cancers, in SLE patients [14]. Clinical studies of patients with systemic sclerosis have also revealed increased risk for lung cancer, non-melanoma skin cancers and breast cancer [19]. Mechanisms contributing to these enhanced cancer risks are largely elusive; however, given pronounced humoral immune responses in afflicted tissues, it is intriguing to speculate that autoantibody–antigen complex formation and deposition in neoplastic microenvironments might contribute. Support for this hypothesis comes from a limited clinical study where advanced colon cancer patients were treated with Rituximab. In these individuals, numbers of CD21-hyperpositive lymphocytes were reduced in parallel with a 50% reduction in tumor burden with no ill-effects as a result of the therapy [20]. Taken together, the clinical data indicate a role for enhanced HI and inflammation, in combination with suppressed CMI, in the pathogenesis of several human cancer types — mechanistic investigation of the molecular and cellular pathways mediating enhanced cancer risk will surely identify new therapeutic targets with which to combat neoplastic disease.

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

HI-associated cytokines as mediators of tumor development

Molecular mechanisms by which HI impacts cancer initiation, promotion and progression are almost certainly multifaceted (Figure 1). Cyt