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Inflammation and Immune Surveillance in Cancer Seminars in Cancer Biology 22 (2012) 23–32 Contents lists available at SciVerse ScienceDirect Seminars in Cancer Biology jou rnal homepage: www.elsevier.com/locate/semcancer Review Inflammation and immune surveillance in cancer a,b b,c,1 a,b,∗,1 Melvyn T. Chow , Andreas Möller , Mark J. Smyth a Cancer Immunology Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia b Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia c Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia a r t i c l e i n f o a b s t r a c t Keywords: Chronic inflammation is a risk factor for tumor development. However, understanding the effect of the Inflammation immune system on tumor development has only been significantly advanced over the past two decades. Immunoediting We now appreciate that the immune system, in addition to tumor-suppressive function by eliminat- Danger signal ing nascent transformed tumor cells, can also exert selection pressure on tumor cells and facilitate Toll-like receptor tumor growth by providing a favorable tumor microenvironment. Yet, the distinctions between tumor- Inflammasome promoting inflammation and tumor-suppressive immunity are still not clear due to the dual role of some cytokines and other molecules in the immune system. The danger signal hypothesis has shaped our view of the role of immunity in cancer development, but still little is known about the exact role of danger sig- nal receptors in cancer progression. In this review, we introduce the processes of cancer immunoediting and inflammation-induced cancer and discuss what is currently known about the role of danger signal receptors in cancer development and progression. © 2011 Elsevier Ltd. All rights reserved. 1. Introduction against the cancer cells. Subsequent work of Osias Stutman and colleagues further fueled this debate. Stutman used the CBA/H The capability and contribution of the immune system to effec- nude mouse strain, the most congenitally immunodeficient mice tively control the cancer growth has been a controversial topic available at the time. He found that the development of methyl- for many years. Paul Ehrlich, in 1909, was one of the first to pro- cholantherene (MCA)-induced sarcomas was not different between pose the concept that the immune system has a critical role in these nude mice and wild-type mice [8]. On the basis of these protecting the host from cancer [1]. He reasoned that otherwise findings, enthusiasm for the validity of the immunosurveillance cancer would occur at a much higher frequency in long-lived ani- hypothesis waned and eventually led to the abandonment of inves- mals. However, this hypothesis was not proven experimentally tigations into this area. However, it is now clear that there were due to the inadequacy of experimental tools and knowledge of important caveats to these early experiments; one of which was detailed immunology at the time. Around the middle of the twenti- that the nude mouse strain used was not completely immuno- eth century the dawning, and then subsequent rapid development, compromised. By the 1990s, the emergence of improved mouse of cellular immunology encouraged Burnet and Thomas to archi- models of immunodeficiency on pure genetic backgrounds allowed tect the “cancer immunosurveillance” hypothesis [2,3]. Subsequent researchers to reassess the validity of the immunosurveillance attempts to prove its validity – to show that a host with an impaired hypothesis. The importance of endogenous interferon-␥ (IFN-␥) in immune system would be more susceptible to tumors – were protecting the host from tumor development was demonstrated ␥ limited to approaches using virus-induced tumors or chemical- [9,10]. These studies showed that neutralization of IFN- in mice induced tumors [4–7]. It was debated whether the controversial resulted in the rapid growth of tumors in the mice [9]. Furthermore, findings could be ascribed to virus-mediated transformation as mice lacking IFN-␥ responsiveness [IFN-␥ receptor or signal trans- a result of defective control of viral infection rather than as a ducer and activator of transcription 1 (STAT1, a transcription factor ␥ consequence of a direct effect of the impaired immune response that is important in regulation of IFN- receptor signaling) were more sensitive to MCA-induced carcinogenesis compared to their wild-type counterparts [10]. Perforin, which is a cytolytic protein in cytotoxic lymphocytes, was also found to have a critical role in inhi- ∗ Corresponding author at: Cancer Immunology Program, Peter MacCallum Can- bition of tumors and in particular, B cell lymphoma development cer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia. [11,12]. These key findings rekindled interest in cancer immuno- Tel.: +61 39656 3728. surveillance. In the last two decades, remarkable advances have E-mail address: [email protected] (M.J. Smyth). 1 These authors contributed equally to this work. been made to demonstrate cancer immunosurveillance and refine 1044-579X/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcancer.2011.12.004 24 M.T. Chow et al. / Seminars in Cancer Biology 22 (2012) 23–32 the hypothesis, with a series of publications demonstrating that by the intensive interaction between immune cells and tumor mice genetically deficient in critical component of the immune sys- cells, eventually induces the formation of tumor cells with reduced tem are more susceptible to spontaneous, transplantable, virus- immunogenicity. These tumor cells are more capable of surviv- or carcinogen-induced tumors [13–17]. The fact that the immune ing in an immunocompetent host, which explains the apparent system has an important role in the control of tumor growth and paradox of tumor formation in immunologically intact individu- metastasis is now a foundation of most cancer immunotherapies. als. Immune-mediated equilibrium has recently been supported by several other important studies in mice [24,25]. As the equi- 2. Cancer immunoediting librium phase involves the continuous eradication of tumor cells and the continuous emergence of resistant tumor cell variants by Why then do cancers occur in immunocompetent individuals immune selection pressure, it is possible that equilibrium is the despite cancer immunosurveillance mechanisms in action? Work longest phase of the three processes in cancer immunoediting. from several groups showed that, in addition to cancer immuno- surveillance, the immune system not only controls tumor quantity, 2.3. Escape but also its quality (immunogenicity) [14,15,18,19]. Tumors that develop in immunocompetent mice often grow more easily than After failure of most intrinsic and extrinsic tumor suppressor tumors that originate from immunocompromised mice, when mechanisms, tumor cells enter the escape phase. Tumor cell escape transplanted into syngeneic immunocompetent mice. This sug- can occur through two major changes that happen either at the gests that the immune system not only protects the host against tumor cell level per se and/or at the level of the tumor microen- tumor formation, but also shapes tumor immunogenicity. Immune vironment. Reduction of the immunogenicity of tumor cells can selection pressure favors the development of less immunogenic lower immune recognition, such as loss of major histocompati- tumors, which escape recognition by a functioning immune system. bility complex (MHC) class I protein that presents the antigens These more recent discoveries led to the formation of the concept of to tumor-specific T cells or other recognition pathways (reviewed “cancer immunoediting”, which is regarded as a refinement of the in [26]). In addition, tumor cells may acquire resistance against cancer immunosurveillance hypothesis [20]. We now view cancer the cytotoxic functions of immune cells, such as expression of immunoediting as a dynamic process composed of three distinct anti-apoptotic molecules preventing tumor cell death (reviewed phases: elimination, equilibrium and escape. in [27]). At the level of the tumor microenvironment, escape may result from the emergence of a complex immunosuppressive net- 2.1. Elimination work within the microenvironment. Dynamic crosstalk between the tumor cells and immune cells can orchestrate this immuno- The elimination phase is a contemporary view of the original suppressive network. Several factors produced by immune cells immunosurveillance hypothesis, in which the innate and adap- and/or tumor cells, including vascular endothelial growth factor tive immune systems work in concert to successfully eradicate ␤ (VEGF), transforming growth factor- (TGF-␤), interleukin (IL)- developing tumors. Infiltration of immune cells into tumors is 10, prostaglandin E2, soluble phosphotidylserines, soluble Fas or a well-documented observation in most, if not all, solid tumors. indoleamine 2,3-dioxygenase, contribute to the establishment of The tumor cell recognition mechanisms employed and how the an immunosuppressive microenvironment (reviewed in [28,29]). naive immune system is activated by transformation remain quite Furthermore, tumors can induce the recruitment of regulatory T poorly understood and our knowledge of these processes as they cells and myeloid derived suppressor cells (MDSC), both that are occur in vivo remains inferred and hypothetical. There may be regulatory immune cells capable
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