Review
Inflammation and immune surveillance in cancer

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Abstract

Chronic inflammation is a risk factor for tumor development. However, understanding the effect of the immune system on tumor development has only been significantly advanced over the past two decades. We now appreciate that the immune system, in addition to tumor-suppressive function by eliminating nascent transformed tumor cells, can also exert selection pressure on tumor cells and facilitate tumor growth by providing a favorable tumor microenvironment. Yet, the distinctions between tumor-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 signal 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.

Introduction

The capability and contribution of the immune system to effectively control the cancer growth has been a controversial topic for many years. Paul Ehrlich, in 1909, was one of the first to propose the concept that the immune system has a critical role in protecting the host from cancer [1]. He reasoned that otherwise cancer would occur at a much higher frequency in long-lived animals. However, this hypothesis was not proven experimentally due to the inadequacy of experimental tools and knowledge of detailed immunology at the time. Around the middle of the twentieth century the dawning, and then subsequent rapid development, of cellular immunology encouraged Burnet and Thomas to architect the “cancer immunosurveillance” hypothesis [2], [3]. Subsequent attempts to prove its validity – to show that a host with an impaired immune system would be more susceptible to tumors – were limited to approaches using virus-induced tumors or chemical-induced tumors [4], [5], [6], [7]. It was debated whether the controversial findings could be ascribed to virus-mediated transformation as a result of defective control of viral infection rather than as a consequence of a direct effect of the impaired immune response against the cancer cells. Subsequent work of Osias Stutman and colleagues further fueled this debate. Stutman used the CBA/H nude mouse strain, the most congenitally immunodeficient mice available at the time. He found that the development of methylcholantherene (MCA)-induced sarcomas was not different between these nude mice and wild-type mice [8]. On the basis of these findings, enthusiasm for the validity of the immunosurveillance hypothesis waned and eventually led to the abandonment of investigations into this area. However, it is now clear that there were important caveats to these early experiments; one of which was that the nude mouse strain used was not completely immunocompromised. By the 1990s, the emergence of improved mouse models of immunodeficiency on pure genetic backgrounds allowed researchers to reassess the validity of the immunosurveillance hypothesis. The importance of endogenous interferon-γ (IFN-γ) in protecting the host from tumor development was demonstrated [9], [10]. These studies showed that neutralization of IFN-γ in mice resulted in the rapid growth of tumors in the mice [9]. Furthermore, mice lacking IFN-γ responsiveness [IFN-γ receptor or signal transducer and activator of transcription 1 (STAT1, a transcription factor that is important in regulation of IFN-γ 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 inhibition of tumors and in particular, B cell lymphoma development [11], [12]. These key findings rekindled interest in cancer immunosurveillance. In the last two decades, remarkable advances have been made to demonstrate cancer immunosurveillance and refine the hypothesis, with a series of publications demonstrating that mice genetically deficient in critical component of the immune system are more susceptible to spontaneous, transplantable, virus- or carcinogen-induced tumors [13], [14], [15], [16], [17]. The fact that the immune system has an important role in the control of tumor growth and metastasis is now a foundation of most cancer immunotherapies.

Section snippets

Cancer immunoediting

Why then do cancers occur in immunocompetent individuals despite cancer immunosurveillance mechanisms in action? Work from several groups showed that, in addition to cancer immunosurveillance, the immune system not only controls tumor quantity, but also its quality (immunogenicity) [14], [15], [18], [19]. Tumors that develop in immunocompetent mice often grow more easily than tumors that originate from immunocompromised mice, when transplanted into syngeneic immunocompetent mice. This suggests

Co-existence of cancer immunoediting and tumor-promoting inflammation

Inflammation normally functions to maintain tissue homeostasis in response to tissue stressors such as infection or tissue damage [32]. Experimental, clinical and epidemiological studies suggest a close association between inflammation and tumorigenesis. Infiltration of leukocytes into tumors was observed by Rudolf Virchow in the 19th century. He was the first to postulate a link between inflammation and cancer. Acute inflammation (i.e., innate immunity) frequently precedes the development of

Tumor-associated inflammation versus therapy-induced inflammation

It is now well established that inflammation has paradoxical roles during tumor development. The net outcome of tumor-associated inflammation depends on the dominance of either tumor-promoting or tumor-suppressive actions. Recently, emerging evidence showed that cancer therapy may induce a strong inflammatory response [45], [46], [47] (Fig. 1). Radiotherapy and some chemotherapies result in substantial tumor cell death, which in turn triggers a local and/or systemic inflammatory response

Danger signals, inflammation and cancer immunoediting

The innate immune system is the first line of host defense against infectious insults and tissue injury. Unlike the adaptive response, which is based on an expansive repertoire of antigen-specific antibodies and T cells with various T cell receptors, innate immunity relies on the recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs)(Fig. 1). The key component of the innate immune system is the pattern recognition receptor (PRR), such as

Conclusions and perspectives

The influence of inflammation on tumorigenesis, and even on cancer therapy, is evidently significant. However, as mentioned above, many of the inflammatory mediators can benefit the host in therapy of tumors despite also having a critical role in cancer development and progression. The dual role of certain molecules is far from being completely understood. Currently, the markers that we use for immune cell phenotyping might not be very useful in functionally differentiating these immune cells

Conflict of interest

The authors declare they have no conflict of interest.

Funding

NH&MRC of Australia.

Victoria Cancer Agency.

Association for International Cancer Research.

Cancer Research Institute.

These funding bodies do not have any part in this manuscripts content.

Acknowledgements

The authors thank Lionel Apetoh for helpful discussions. This work was supported by the National Health and Medical Research Council of Australia (NH&MRC) Program Grant (454569), the Victorian Cancer Agency, and the Association for International Cancer Research (AICR). AM was supported by a NBCF Research Fellowship. MJS received support from a NH&MRC Australia Fellowship. MTC was supported by a Cancer Research Institute PhD scholarship.

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