ReviewInflammation and immune surveillance in cancer
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.
References (186)
- et al.
Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN-γ receptors
Immunity
(1994) - et al.
Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis
Blood
(2001) - et al.
NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy
Immunity
(2008) - et al.
MHC antigens and cancer: implications for T-cell surveillance
Curr Opin Immunol
(1992) Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators
Semin Cancer Biol
(2006)Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention
Semin Cancer Biol
(2006)- et al.
Immunity, inflammation, and cancer
Cell
(2010) - et al.
Inflammation and cancer: back to Virchow
The Lancet
(2001) TGFβ in cancer
Cell
(2008)- et al.
Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter
Dev Cell
(2010)
HMGB proteins and gene expression
Curr Opin Genet Dev
Monocytes promote natural killer cell interferon gamma production in response to the endogenous danger signal HMGB1
Mol Immunol
Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells
Blood
Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule
Am J Pathol
Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein
J Biol Chem
A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA
Blood
Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer
Biochem Biophys Res Commun
Interleukin-1 and IL-23 induce innate IL-17 production from γδ T Cells, amplifying Th17 responses and autoimmunity
Immunity
Tumor-specific Th17-polarized cells eradicate large established melanoma
Blood
Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism
Blood
Endogenous IL-17 contributes to reduced tumor growth and metastasis
Blood
Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts
Osteoarthritis Cartilage
Interleukin-17 stimulates the expression of IκBα mRNA and the secretion of IL-6 and IL-8 in glioblastoma cell lines
J Neuroimmunol
Interleukin-17 promotes angiogenesis and tumor growth
Blood
Does IL-17 suppress tumor growth
Blood
Host–pathogen interactions in sepsis
Lancet Infect Dis
Ueber den jetzigen stand der Karzinomforschung
Ned Tijdschr Geneeskd
Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications
Br Med J
Cellular and humoral aspects of the hypersensitive states
Neonatal thymectomy and non-viral mammary tumours in mice
Nature
Effect of neonatal thymectomy on the induction of sarcomata in C57 BL mice
Nature
Immunologic properties of methylcholanthrene-induced sarcomas of neonatally thymectomized mice
J Natl Cancer Inst
Long-term spontaneous tumor incidence in neonatally thymectomized mice
J Immunol
Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice
Science
Demonstration of an interferon-γ-dependent tumor surveillance system in immunocompetent mice
Proc Natl Acad Sci
Decreased tumor surveillance in perforin-deficient mice
J Exp Med
Perforin-mediated suppression of B-cell lymphoma
Proc Natl Acad Sci
Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma
J Exp Med
IFN and lymphocytes prevent primary tumour development and shape tumour immunogenicity
Nature
Differential tumor surveillance by natural killer (NK) and NKT cells
J Exp Med
Regulation of cutaneous malignancy by γδ T cells
Science
Chemically induced sarcomas from nude mice are more immunogenic than similar sarcomas from congenic normal mice
Eur J Immunol
MCA sarcomas induced in scid mice are more immunogenic than MCA sarcomas induced in congenic, immunocompetent mice
Scand J Immunol
Cancer immunoediting: from immunosurveillance to tumor escape
Nat Immunol
HMGB1 and RAGE in inflammation and cancer
Annu Rev Immunol
Adaptive immunity maintains occult cancer in an equilibrium state
Nature
Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells
J Exp Med
Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma
J Clin Invest
Mechanisms of apoptosis avoidance in cancer
Curr Opin Oncol
Regulatory T cells, tumour immunity and immunotherapy
Nat Rev Immunol
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These authors contributed equally to this work.