Humoral immunity, inflammation and cancer Ting-Ting Tan 1 and Lisa M Coussens 1,2,3 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 immu- notherapeutics 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 pro- motion 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 cyto- kines 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 blad- der 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 infiltra- tions 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 www.sciencedirect.com Current Opinion in Immunology 2007, 19:209–216