(2008) 27, 5913–5919 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc REVIEW Cytokine-based transformation of immune surveillance into tumor-promoting inflammation

JB Mumm and M Oft

Department of Oncology, Schering-Plough Biopharma (formerly DNAX), Palo Alto, CA, USA

During the last decade, it has become clear that the species released by the inflammatory cells may increase mammalian is able to recognize and the mutation rate in the proliferating epithelial stem partially suppress nascent tumors. Human T cells specific cells. provides another key condition for to and onco-fetal are present in human tumor formation and promotion with molecular links to patients and their tumors. At the same time, inflammation. Although the tumor-promoting function molecular links between tumor-associated inflammation of angiogenesis is now well established (Folkman, 2007), and tumor progression have been uncovered, providing an remarkably one of pathologist’s five hallmarks of explanation for the long recognized epidemiological link inflammation for centuries has been rubor (lat. for between inflammation and cancer. The synopsis of these redness) or angiogenesis. Therefore, before and even in findings suggests a new interpretation of tumor immunity. the absence of any selective pressure exerted by an It appears that recognition or antigen-specific T- adaptive , there are multiple valid cell expansion at large is not as profoundly impaired in explanations why tumor cells would originate, survive tumor patients as the correct polarization, the survival and and thrive in a nutrient-rich environment like a the effector function of tumor-infiltrating T cells. This chronically inflamed tissue. review will focus on pro-inflammatory cytokines likely to The initial observations of antigen-specific recogni- contribute to the deregulation of tumor-specific immunity tion of human tumors by CD8T cells were made more and its consequences. than 20 years ago, followed by the cloning of the first Oncogene (2008) 27, 5913–5919; doi:10.1038/onc.2008.275 definitive tumor antigens (Knuth et al., 1984; van der Bruggen et al., 1991). Since then, it has become clear Keywords: IL-23; IL-12; Th17; inflammation; tumor that the human immune system recognizes the antigenic immune surveillance profile of tumors relatively well (Van Der Bruggen et al., 2002; Jager et al., 2003). The infiltration of cytotoxic T cells into tumor tissue is limited however, and T-cell infiltration into tumors correlates with an improved Introduction prognosis for the patient (Naito et al., 1998; Galon et al., 2006). To overcome this limitation, therapies have Tumors often arise at the site of chronic inflammation. been developed to expand the repertoire of tumor- Examples include Helicobacter-associated gastric can- specific T cells in patients, either by antigen-specific cer, chronic colitis fueling the development of colon vaccines or by adoptive transfer of in vitro expanded cancer and the chronic bronchitis of smokers lungs cytotoxic T cells. However, even significant expansions giving rise to lung cancer to list a few (Coussens and of the numbers of circulating tumor-specific T cells do Werb, 2002; Lin and Karin, 2007). Possible explanations not often translate into long-term therapeutic benefits for this epidemiological paradigm are multifold. (Dudley et al., 2002), even when the antigens recognized Increased tissue regeneration during inflammatory by the expanded and activated T cells are still expressed responses to chronic damage or infection may provide in the tumor (Rosenberg et al., 2005). It is important to a constant need for tissue regeneration. The resulting note that the induced or transferred T cells are compensatory epithelial cell proliferation induced to sufficiently specific and sensitive to eliminate malignant regenerate lost or damaged tissues might lead to an cells in vitro but frequently fail to do so in the patient. In increased chance of multiple mutations and a prolif- experimental mouse models, appropriate stimulation or erative advantage for the cells carrying those mutations. resurrection of nascent immune surveillance appears In fact, the amount of cell loss and the subsequent capable of eliminating not only the tumor cells but also regeneration correlate in mouse models of liver cancer to tumor-promoting stroma (Blankenstein, 2005). The tumor growth (Maeda et al., 2005). Also, radical oxygen latter successes are mostly observed in small and early tumors, whereas well-established and clinically relevant stages of mouse tumors escape the same immune Correspondence: Dr M Oft, Department of Oncology, Schering- Plough Biopharma (formerly DNAX), 901 California Avenue, Palo therapy. Alto, CA 94303, USA. We have recently suggested that the very regulation of E-mail: [email protected] tissue-regenerating inflammation might directly inhibit Cytokine-based transformation of immune surveillance JB Mumm and M Oft 5914 cytotoxic -mediated destruction of tumor cells and most other cells within the tumor microenvironment within the inflamed tissue (Langowski et al., 2007). As a (Szlosarek et al., 2006). TNF-a as well as IL-1 are consequence, immune surveillance against tumors is essential effector cytokines for the initiation and largely prevented in the local environment by pro- maintenance of chronic inflammation in mouse models inflammatory mediators such as interleukin (IL)-23 of immune-mediated disorders such as rheumatoid (Langowski et al., 2006). arthritis (Williams et al., 2000). The relevance of this As described above, a solid body of evidence links pathway for human disease is best exemplified in the increases in tumor incidence with inflammation. In success of anti-TNF-a therapies in inflammatory dis- addition, clinical and experimental findings also link eases (Feldmann and Maini, 2001). TNF-a also induces tumor progression to the upregulation of pro-inflam- in activated tumor-infiltrating T cells, and matory molecules, particularly during the late stages of therefore may function to blunt the immune surveillance cancer progression and during tumor cachexia (Balkwill against tumors within the tumor itself. Although the et al., 2005). Several of the cytokines linked to tumor- pro-apoptotic effects of TNF-a spiked interest in its promoting inflammation such as -a therapeutic utility, it requires higher concentrations (TNF-a), transforming growth factor-b (TGF-b), IL-6 than therapeutically achievable (Mocellin et al., 2005). and IL-23 are functionally linked to the newly dis- Most animal models and clinical studies revealed covered Th17 CD4 þ helper cell lineage. the pro-neoplastic functions of TNF-a rather than its In this review, we will attempt to summarize the tumor- pro-apoptotic functions on tumor cells. centric cytokine network and its simultaneous influence Tumor necrosis factor-a produced by tumor cells or on effector cell populations involved in the tumor- inflammatory cells may promote tumor survival via the associated inflammatory response and immune surveil- induction of antiapoptotic genes controlled by nuclear lance of tumor development and progression (Figure 1). factor-kB activation. Indeed, TNF-a has been demon- strated to promote tumorigenesis as TNF-a-deficient mice or mice treated with anti-TNF-a antibodies are largely protected from the chemical induction of skin Dual role for TNF-a in cancer? papillomas (Moore et al., 1999; Scott et al., 2003). TNF-a may also directly contribute to neoplastic transforma- Tumor necrosis factor-a is a trimeric cytokine produced tion by stimulating production of genotoxic reactive by activated and pro-inflammatory T cells. oxygen species and nitric oxide (Szlosarek et al., 2006). TNF-a can stimulate both pro-and antiapoptotic In humans, higher concentrations of TNF-a are signals in tumor cells, endothelial cells, macrophages found in the serum of cancer patients compared to

Worms Microbes Parasites memory Viruses acute Tumors? Tumors?

Th IL-4 Th 2 IL-5 1 B cells, IL-12 Mast cells IFN- Eosinophils IL-13 T cells IL-18 IL-10

Immune Stimulation

IL-1 IL-10 IL-6 IL-17 IL-23 T reg Th17

Tissue damage Anti-inflammatory resolution Cytokines activated in human tumors, associated emergency with poor prognosis and / or reduced survival Figure 1 Tumor-induced deregulation of the pathogen-directed immune regulation. Exposure to novel antigens in an inflammatory milieu stimulates antigen-specific immune responses. The composition of the cytokine milieu, however, regulates which effector molecules and cells are deemed appropriate to eliminate the challenge, like a nascent or metastasizing tumor. The activation of inappropriate cytokine cascades might not only inhibit efficient elimination of tumor cells but also contribute to immune pathologies, promoting tumor growth by providing essential growth environment. Green: cytokines activated in human cancer tumors associated with decreased prognosis or short survival of human patients. Circle: effector cells.

Oncogene Cytokine-based transformation of immune surveillance JB Mumm and M Oft 5915 control subjects, and elevated TNF-a concentrations in macrophages and T cells to engender an inflammatory the serum also correlate with decreased prognosis milieu similar to chronic inflammatory diseases but for the patients (Szlosarek and Balkwill, 2003). Finally, deficient in cytotoxic cells such as CD8T cells and TNF-a is closely associated with tumor-induced natural killer cells. TGF-b is one of the first proteins cachexia, an inflammatory multiorgan failure in the late released from platelets after a vascular lesion, induces stage of cancer patients, and with the inflammatory angiogenesis (Roberts et al., 1986) and is a potent paraneoplastic syndromes associated with tumors chemoattractant for granulocytes and monocytes (Wahl like . Genetic polymorphisms confer- et al., 1987; Brandes et al., 1991); TGF-b also limits the ring higher TNF-a production are associated with phagocytic and opsonizing activity of those innate increased risk of a variety of human (Szlosarek responders. More importantly, although TGF-b pro- et al., 2006). Excitingly, renal cell cancer patient motes the development of Langerhans cells and den- treated in a phase II clinical study with anti-TNF-a dritic cells from hematopoietic progenitors (Borkowski antibodies experienced clinical benefits (Harrison et al., et al., 1996; Strobl et al., 1996), it inhibits the 2007). maturation, antigen presentation and costimulation by both macrophages and dendritic cells (Li et al., 2006). Such immature dendritic cells produce large amounts of TGF-b and might efficiently prime regulatory CD4 þ Inflammation control by TGF-b T cells (Treg). TGF-b is required for the development of Tregs, and TGF-b expression by Tregs is essential for Another key regulator of inflammatory processes tightly their proliferation and function. Regulatory T cells are associated with chronic inflammation and cancer is found in human tumors and their presence correlates TGF-b. Although considered to be primarily anti- again with a poorer prognosis (Curiel et al., 2004). In a inflammatory, TGF-b contributes to the inflammatory new twist of the development of helper T-cell lineages, it milieu of tumor mediators and cell types facilitating has become clear that pro-inflammatory IL-17-produ- tissue remodeling as well as direct local suppression of cing Th17T cells share a common path with regulatory antigen-specific CD8T cell function. T cells. Although the presence of TGF-b favors a Transforming growth factor-b is a pleiotropic cyto- regulatory fate of naive T cells, simultaneous presence kine that exerts effects on most cell types in a tumor of TGF-b and IL-6 fosters the differentiation of a pro- thereby simultaneously impacting immunological and inflammatory T cell expressing IL-6 and IL-17 among non-immunological processes. TGF-b activates a hetero- other cytokines (Bettelli et al., 2006). Given the tight dimeric receptor pair of TGF-b receptors I and II association of IL-6 with tumor incidence and progres- (TbRI/II). Upon ligand binding, TbRI directly phos- sion (see below), naive T cells entering an established phorylates the transcription factors Smad2 and Smad3, tumor are more likely to be exposed to conditions which shuttle to the nucleus to induce transcription favoring Th17 differentiation. Indeed, it has been shown (Letterio, 2005). TGF-b is released not only by a variety that Th17 are present in large numbers in human and of cells in human and mouse tumors including macro- mouse tumors (Kryczek et al., 2007). phages, platelets and T cells (Kehrl et al., 1986; Roberts Transforming growth factor-b not only restricts the et al., 1986), but also by the tumor cells themselves. proliferation of naive CD4 þ T cells by suppressing IL-2 Early in the development of cancer and in premalignant production in T cells but also antagonizes both Th1 and lesions, TGF-b plays a tumor suppressive function due Th2 effector differentiation (Li et al., 2006). At the same to its inhibition of tumor cell growth. Genetic deletion time, however, TGF-b protects T cells from apoptosis of the TGF-b receptor in genetic mouse models for during T-cell expansion and differentiation. In particu- human cancer leads to increased tumor incidence and lar, TGF-b inhibits activation-induced cell death of T progression (Bierie and Moses, 2006). Interestingly, cells (Zhang et al., 1995). Polyclonal T-cell activation in ablation of TGF-b signaling in the tumor cells leads to mice using activating anti-CD3 antibodies leads to an increased level of TGF-b in the tumor and increased widespread apoptosis of both CD4 and CD8 þ T cells number of TGF-b-producing CD11b þ GR-1 þ mye- in TGF-b1À/À mice (Chen et al., 2001). Similarly to loid cells in the tumor stroma (Yang et al., 2008). helper T cells, CD8 þ cytotoxic T cells are inhibited in However, most human tumors thrive in the presence of their proliferation and differentiation by TGF-b (Wrze- large amounts of TGF-b while retaining the TGF-b sinski et al., 2007). TGF-b inhibits the expression of signaling pathways. The exception appears to be cytokines like interferon-g (IFN-g) and cytotoxic of the where muta- effector molecules such as perforin, and also the tions in either the TGF-b receptor or the Smads render exocytosis of the cytotoxic granules (Li et al., 2006). the tumor cells insensitive to abundant TGF-b (Derynck Moreover, when stimulated with both IL-6 and TGF-b, et al., 2001). Autocrine TGF-b regulation in tumor CD8T cells not only cease expression of IFN-g and lose cells plays an important role during invasion, metastasis their cytotoxicity but are also induced to secrete IL-17 and epithelial–mesenchymal transition of tumor cells (Liu et al., 2007). IFN-g induces major histocompat- (Oft et al., 2002). In addition, many of the tumors ibility complex I in both dendritic cells and tumor cells; promoting effects of TGF-b involve paracrine regula- therefore, replacing IFN-g with IL-17 in the tumor tion of inflammation and tissue remodeling. TGF-b milieu might have severe consequences for immune modifies the activities of fibroblasts, endothelial cells, recognition and surveillance.

Oncogene Cytokine-based transformation of immune surveillance JB Mumm and M Oft 5916 The pro-inflammatory cytokine IL-6 promotes tumor Nakae et al., 2003). While IL-6-deficient animals show a growth partial resistance to chemical-induced skin tumors (Ancrile et al., 2007); the absence of IL-23 renders Interleukin-6 engages the heterodimeric receptor com- animals completely protected from tumors (Langowski plex of 130 (gp130) and IL-6 receptor-a et al., 2006). (IL-6Ra). While gp130 is expressed in the signal- receiving cell, the IL-6Ra subunit can be either membrane bound or supplied as a soluble receptor (sIL-6Ra) by an accessory cell, via a process known as Inflammation control by IL-23 and IL-12 in cancer trans-signaling (Rose-John et al., 2006). IL-6 induces the phosphorylation of both STAT3 and STAT1. The Interleukin-23 and IL-12 are closely related heterodi- involvement of both IL-6 and STAT3 in malignant cell meric pro-inflammatory cytokines with similar struc- survival and proliferation has been well documented in tures, similar cellular sources and cellular targets but numerous experimental systems (Aggarwal et al., 2006; opposing functions. They are composed of a shared p40 Rose-John et al., 2006). Through the activation of genes subunit, structurally related to cytokine receptors, and involved in cell cycle progression and suppression of a unique subunit, IL-23p19 or IL-12p35, structurally apoptosis, IL-6 can directly protect tumor cells from four-helix bundle cytokines (Kastelein et al., 2007). apoptosis. IL-6 has also been shown to act as an IL-12 uses the heterodimeric receptors IL-12Rb1 and autocrine growth factor for tumors (Baffet et al., 1991). IL-12Rb2, whereas IL-23 activates IL-12Rb-1/IL-23R IL-6 is essential in the initiation and maintenance of dimers (Parham et al., 2002). Like IL-12, IL-23 induces chronic inflammation of the colon (Atreya et al., 2000). TYK2-and JAK2-mediated phosphorylation of the Trans-signaling of IL-6 is similarly essential for the transcription factors STAT1, STAT3 and STAT5, the development of inflammation-induced colon tumors phosphorylation of STAT4 being to a lesser extent (Becker et al., 2004). Finally, antibody-mediated inhibi- (Parham et al., 2002; Trinchieri, 2003). The receptors for tion of IL-6 delays the development of chemically both IL-12 and IL-23 are primarily expressed on T, induced colitis-associated colon cancer (Becker et al., natural killer and natural killer T cells, with low levels 2004). present on monocytes, macrophages and dendritic cells. Interleukin-6 levels are elevated in the serum and Both cytokines are produced primarily by activated tissue of cancer patients with multiple myeloma, renal antigen-presenting cells in response to bacterial products cell, ovarian, colon, breast or prostate cancers. The IL-6 (Trinchieri et al., 2003). Consequently, IL-12p40-defi- serum levels correlate negatively with the prognosis in cient mice, lacking IL-12 and IL-23, are highly breast and prostate cancer patients (Smith et al., 2001; susceptible to numerous bacterial, fungal and parasite Rao et al., 2006). IL-6Ra is highly expressed on tumor infections including Salmonella, Citrobacter, Cryptococ- cells, with some evidence for shedding of the sIL-6Ra to cus and Leishmania species (Bowman et al., 2006). For stimulate trans-signaling in cells not expressing IL-6Ra the response against most of these pathogens, IL-12- (Becker et al., 2004; Rose-John et al., 2006). IL-6 may mediated responses are essential, whereas the IL-23 also be a cancer-predisposing genetic risk factor, with contribution is often only detected in the simultaneous IL-6 promoter polymorphisms leading to higher IL-6 absence of IL-12 (Kastelein et al., 2007). Instant lethal expression leading to a worse prognosis for colon cancer doses of Klebsiella or Citrobacter, however, require patients (Landi et al., 2003). IL-23-mediated host responses in mice (Happel et al., In combination with TNF-a, IL-6 stimulates the 2003; Mangan et al., 2006). Surprisingly, these suscept- expansion and cytotoxicity of naive CD8T cells in vitro ibilities have not been described for IL-12p40- or (Sepulveda et al., 1999); however, IL-6Ra has been IL12Rb1-deficient humans who suffer exclusively from shown to be downregulated upon activation in naive mycobacterial and salmonella infection but show and memory T cells (Betz and Muller, 1998), suggesting normal resistance to most other pathogens, including that its potential stimulatory effect on tumor-infiltrating viruses (Novelli and Casanova, 2004). effector lymphocytes may be lost. Recently, however, it IL-12 treatment in preclinical tumor models has become clear that IL-6 together with TGF-b is promotes immune surveillance against transplanted crucial for the induction of IL-17-producing Th17 syngeneic tumors by inducing IFN-g-producing Th1 helper cell lineage (Mangan et al., 2006; Wilson et al., cells and the proliferation and cytotoxic activity of 2007). It remains to be tested how many of the CD8 þ T cells and natural killer cells. IL-12-induced effects of IL-6 in the regulation of tissue inflammation IFN-g is not only rate limiting for T-cell activity but and cancer are dependent on the induction and also induces the expression of major histocompatibility subsequent control of this T-cell lineage. Importantly, complex I and thereby allows increased recognition of it has been shown that the pro-inflammatory T helper tumor antigens (Wong et al., 1984). Tumor immune cells continue to express both IL-17 and IL-6 (Becker surveillance in mouse models is largely dependent et al., 2004; Langrish et al., 2005). In inflammatory on IFN-g-expressing T cells (Kaplan et al., 1998). disease models, deficiency of IL-17 ameliorates the Similar experiments using IL-23 expressed in the disease, deficiency of both IL-6 or IL-23, a cytokine transplanted tumor cell or systemically were equally controlling the activity of Th17 cells, protected animals efficient in rejecting syngeneic transplanted tumors from disease (Alonzi et al., 1998; Cua et al., 2003; (Lo et al., 2003).

Oncogene Cytokine-based transformation of immune surveillance JB Mumm and M Oft 5917 Interleukin-12 is therefore generally considered to proliferation and maturation further fueling the innate promote antitumor effects, and cancer patients have immune activation (Kolls and Linden, 2004). IL-17- been treated with recombinant IL-12 in several clinical producing CD8 and CD4 þ T cells have recently been studies (Atkins et al., 1997). Dose-limiting toxicities reported to be widely present in human and mouse were, however, observed before clinical benefits had tumor microenvironments (Kryczek et al., 2007). It has been achieved. The toxicities appeared to be IFN-g- also been suggested that CD8 T cells expressing IL-17 associated and were most likely the manifestations of a largely lack cytotoxic capacity (Liu et al., 2007). It is systemic immune response. Subsequent attempts com- important to note that IL-23 can induce, independent of bining IL-12 therapy with a peptide vaccine have so far IL-17, angiogenic erythema, inflammation and kerati- not revealed enhanced clinical benefits in the IL-12 nocyte hyperproliferation, phenocopying aspects of treatment arms (Cebon et al., 2003). human psoriatic lesions (Chan et al., 2006). Psoriatic The difference in IL-12 and IL-23 function against disease does not correlate with increased incidence of bacteria or tumors in mice and in man might be a (Rohekar et al., 2008). The IL-23-mediated reflection on the amount of infectious particles or the physiological changes in the skin, however, strikingly antigenic dose challenging the host defense. Most mouse resemble the microenvironment observed in early models frequently use systemic exposure of the host to malignant lesions millions of colony-forming units of bacteria and viruses or injections with large numbers of tumor cells. Immune recognition of human tumors might, however, follow a quite different kinetic, with only limited antigen Conclusions exposure at first. The majority of infections in human patients are similarly not characterized by initial For decades, chronic inflammatory conditions have exposure to large numbers of infectious particles. been observed in association with tumor incidence, However, there are also striking differences in the tumor progression and detrimental prognosis in human regulation of immune surveillance to tumors in either cancer patients. IL-12- or IL-23-deficient animals. IL-12 deficiency Only recently have we begun to understand the increases not only the incidence of tumors but also molecular mechanisms of how and why tumors occur allows for rapid tumor growth in mice. In contrast, more frequently in an inflammatory microenvironment deficiency in IL-23 or the IL-23 receptor not only or in an inflammation-plagued host. Pro-inflammatory dramatically reduces tumor incidence but also reduces cytokines are not surprisingly at the crossroad of this tumor growth of established tumors (Langowski et al., deregulation. As described above, several of these cyto- 2006). In the local tumor microenvironment, IL-23 not kines are highly expressed in human cancers (Figure 1) only induces the hallmarks of chronic inflammation and do alter the adaptive immune response in ways that such as metalloproteases, angiogenesis and are simultaneously beneficial to tumor growth. Antigen- infiltration, but also reduces antitumor immunosurveil- specific cytotoxicity, in particular by CD8T cells, is lance by locally suppressing the presence of CD8T cells. blunted, whereas the inflammation responses to the same In contrast, the absence of IL-12 leads to exacerbation tumor antigen are unaltered and even enhanced. Several of the myeloid-driven inflammation with a coincident of the cytokines essentially involved in the inflammatory lack of CD8 T cells (Langowski et al., 2006). Interest- regulation are either fueled by Th17 CD4 þ Tcellsor ingly, it is IL-23p19 and IL12p40 that are found to be foster their development. Therapeutic expansion of the overexpressed in the majority of human cancers, not tumor antigen-specific immune response might therefore IL-12p35. fail to eliminate the tumor but stimulate tumor-specific In mouse models of autoimmune diseases, IL-23 but non-cytotoxic inflammation. induces chronic inflammation in part through the It is tempting to speculate that the observed derailing stimulation of innate myeloid effector cells and stromal of antitumor immunity into an inflammatory response is activation, and many aspects of IL-23-dependent tissue at its core, a defensive strategy of the tumor, selected for inflammation can be recapitulated in the absence of independently of the tumor cell transformation. Alter- T cells (Uhlig et al., 2006). natively, it might be the mere result of, and the default However, IL-23 also controls the activity of Th17 reaction to, the expression of transforming oncogenes T cells. Although Th17 develop from naive T cells under within the tumor cell. Third, the presence of mutant cell the influence of TGF-b and IL-6, they subsequently clones in an inflamed and regenerating tissue could require IL-23 to suppress endogenous IL-10 and become simply be an unfortunate coincidence. Here, the tumor proficient in their pro-inflammatory function (McGea- cell would take advantage of the improved cytokine- chy et al., 2007). This pro-inflammatory function mediated growth conditions for the nascent tumor, orchestrates inflammatory tissue destruction by the whereas the same cytokines such as IL-23 inhibit the adaptive immune system. The induction of IL-17 by immune-mediated tumor surveillance and tumor cell IL-23 in tumors is an attractive prospect because IL-17 elimination. promotes angiogenesis in a variety of models and It remains to be seen if anti-inflammatory molecules induces matrix metalloproteinases, two events that can deliver therapeutic benefit to patients suffering from potentiate tumor growth (Numasaki et al., 2003). large tumors, rather than serving merely a prophylactic In addition, IL-17 controls chemotaxis, role potentially preventing cancer occurrence.

Oncogene Cytokine-based transformation of immune surveillance JB Mumm and M Oft 5918 References

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