Protumor Vs Antitumor Functions of IL-17

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Protumor vs Antitumor Functions of IL-17 Gopal Murugaiyan and Bhaskar Saha J Immunol 2009; 183:4169-4175; ; This information is current as doi: 10.4049/jimmunol.0901017 of September 30, 2021. http://www.jimmunol.org/content/183/7/4169 Downloaded from References This article cites 114 articles, 54 of which you can access for free at: http://www.jimmunol.org/content/183/7/4169.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Protumor vs Antitumor Functions of IL-171 Gopal Murugaiyan* and Bhaskar Saha2†

Inflammation appears to be a necessity for both metas- Although CD40-induced IL-12 is required for the induction of tasis and elimination of tumor cells. IL-17, a proinflam- Th1, the inflammatory Th subset, lack of CD40 did not seem to matory cytokine produced by Th17 cells, contributes to impair Th1 response as much as expected and mediated the auto- both the processes by playing a dual role in the antitu- immune diseases (15, 16). Mice deficient in the IL-12 subunit p35 mor immunity. On one hand, IL-17 promotes an anti- lack functional IL-12 and are still susceptible to experimental au- tumor cytotoxic T cell response leading to tumor regres- toimmune encephalomyelitis (EAE). In contrast, p19-deficient mice are deficient in functional IL-23 and are resistant to EAE sion. On the other hand, by facilitating angiogenesis and (17). Further investigation into these discrepancies led to the dis-

ϩ Downloaded from egress of tumor cells from the primary focus, IL-17 pro- covery of IL-17-producing CD4 T cells that were later named motes tumor growth. Thus, the therapeutic application Th17 cells. In this review, we will discuss how IL-17 also contrib- that uses IL-17 needs to be refined by minimizing its utes to the antitumor immunity rather dually, although its major protumor functions. The Journal of Immunology, function may be to mediate inflammation. 2009, 183: 4169–4175. IL-17, IL-17 receptors, and Th17 cells

The cytokine IL-17, originally termed CTLA-8, was isolated as http://www.jimmunol.org/ hronic inflammation is associated with increased tu- a CD4-specific transcript from a rodent cDNA library (18). mor metastasis, but the mechanism of the association Later on, human IL-17 and the IL-17 receptor, IL-17R, were C remains unknown. Hypoxia is proposed to be the trig- discovered (19–21). With the discovery of new cytokines that gering factor. As the tumor cells grow in mass, the core of the resemble it, IL-17 became the founding member of a new cy- tumor suffers from hypoxia that triggers a chain of events lead- tokine family composed of six cytokines and five receptors (Ta- ing to increased intratumoral vasculature. These vessels func- ble I and Refs. 22–25). IL-17 is secreted primarily by Th17 cells tion as countercurrent conduits, helping the tumor cells metas- as a homodimer and can be both nonglycosylated and N-glyco- tasize out of the tumor and supplying not only nutrients but sylated. In addition to Th17 cells, IL-17 can also be produced by guest on September 30, 2021 ϩ also immune cells into the tumor mass (1). Thus, the inflam- by cells other than Th cells, such as invariant NKT cells, CD8 mation serves two counteracting functions: promoting tumor T cells, and ␥␦-T cells (26–28). The cytokine has pleiotropic growth and antitumor immunity. Effective antitumor immu- functions with multiple targets. IL-17R has a single trans-mem- nity depends primarily on T cells. Although IFN-␥-secreting brane domain with a long cytoplasmic tail, implying the exis- Th1 cells and CTLs mediate antitumor immunity, the other T tence of multiple regulatory domains such that receptor signal- cell subsets such as Foxp3-expressing regulatory T cells (Treg)3 ing may trigger diverse functions. Discrepancies between IL-17 and IL-10-secreting regulatory type 1 (Tr1) cells dampen im- binding constants and the concentrations needed to evoke bio- munity to tumor-associated Ags and represent the main hurdle logical responses imply an additional subunit in IL-17R signaling (22, 23, 25). Although IL-17R expression is ubiquitous, in successful antitumor immunotherapy (2–4). In addition, the most of the studies have been performed on fibroblasts, osteo- IL-17-secreting Th subset (Th17) promotes inflammation and blasts, and epithelial cells. However, the structure-function re- thus may promote both tumor growth and tumor regression. lationship is not available for either the cytokine or its receptor. Similarly, CD40, a costimulatory receptor that plays important Because Th17 cells produce large quantities of IL-17A, most roles in the induction of Th1 cells and CTLs (5–9) is also shown to Th17-mediated effects are attributed to this cytokine. Many play dual role not only in tumors (10–12) but also in Leishmania factors are required for the induction and stabilization of Th17 infection (13, 14). Thus, any factors that play dual roles, such as cells. Of these, TGF-␤ and IL-6 are the most crucial cytokines CD40 or IL-17, in promoting both tumor growth and antitumor for its differentiation. IL-6 induces the production of IL-21, immunity need to be studied in depth to minimize their protumor which subsequently favors Th17 differentiation in an autocrine effects and thereby enhance the antitumor effects. manner (29, 30). These cells require CD40-induced IL-23 to

*Center for Neurologic Diseases, Brigham and Women’s Hopsital and Harvard Medical 2 Address correspondence and reprint requests to Dr. Bhaskar Saha, Scientist-F, National School, Boston, MA 02120; and †National Centre for Cell Science, Ganeshkhind, Pune, Centre for Cell Science, Ganeshkhind, Pune 411007, India. E-mail address: sahab@ India nccs.res.in Received for publication May 28, 2009. Accepted for publication August 10, 2009. 3 Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; ROR, retinoid orphan receptor; VEGF, vas- The costs of publication of this article were defrayed in part by the payment of page charges. cular endothelial growth factor. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 1 The work was supported by the Department of Biotechnology, Government of India. www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901017 4170 BRIEF REVIEWS: IL-17 AND CANCER

Table I. IL-17 and IL-17 receptor superfamily: ligands, receptors, and functions

Cytokine Chromosomes Cellular Sources Receptors Major Functions

IL-17A (CTLA8) 6p12 Memory T cells IL-17RA, IL-17RC Neutrophil recruitment, cytokine induction, inflammation IL-17B 5q32-34 Multiple tissues IL-17RB Inflammation IL-17C 16g24 Unknown Unknown Modulation of Th1 cytokine production IL-17D 13q12.11 Multiple tissues Unknown Cytokine secretion IL-17E (IL-25) 14q11.2 Th2 IL-17RB Modulation of Th2 cytokines IL-17F (ML-1) 6p12 CD4ϩ T, monocytes IL-17RA, IL-17RC Angiogenesis maintain their Th17 phenotype in vivo. The differentiation of antagonizing Th1 differentiation and CTL functions such as Th17 cells that secrete IL-17 requires the expression of the tran- perforin production (57). Upon stimulation with TGF-␤ and ϩ scription factor ROR-␥t (where ROR is retinoic orphan recep- IL-6, CD8 T cells not only lose their cytotoxic ability but are ϩ tor; Ref. 31). The induction of ROR-␥t is dependent on also induced to secrete IL-17 (58). Th1 or CD8 T cell-ex- STAT-3, which is preferentially activated by IL-6, IL-21, and pressed IFN-␥ inhibits angiogenesis and induces MHC class I IL-23. STAT-3-deficient T cells impair Th17 differentiation, molecules in tumor cells, thus favoring immune recognition whereas overexpression of a constitutively active form of and the subsequent arrest of tumor growth (59). In contrast, STAT-3 increases IL-17 production. STAT-3 affects ROR-␥ IL-17 favors angiogenesis and tumor growth; therefore, replac- Downloaded from expression and binds to the IL-17 and IL-21 promoters. Thus, ing IFN-␥ with IL-17 in the tumor microenvironment may STAT-3 and ROR-␥t regulate IL-17 production in a coordi- have severe consequences for immune recognition and surveil- nated manner (Fig. 1). lance. Indeed, the presence of a tumor secreting both IL-6 and ϩ It has been shown that Th17 cells are gradually increased in the TGF-␤ causes local polarization or expansion of CD8 T cells tumor microenvironment during tumor development. In addi- into an IL-17 secreting state (Tc17). Because IL-17 could po- tion, Th17 cells have been found in various tumors, including my- tentially promote tumor cell survival, it is possible that the IL- http://www.jimmunol.org/ ϩ cosis fungoides, Se´zary syndrome, prostate, and gastric cancer (Ta- 17-producing CD8 T cells may promote tumor growth (53). ble II; Refs. 32–52). Many factors released by the tumor cells and In a developing tumor, IL-17 production is further enhanced the tumor stroma or molecules secreted by tumor-infiltrating im- by the reciprocal regulation of IL-12 and IL-23 by PGE2, the ␤ mune cells such as TGF- , IL-6, PGE2, IL-21, IL-23, osteopontin, most abundant prostanoid in epithelial cell tumors (60). Al- IL-1␤, and TNF-␣ can play major roles in the induction of Th17 though IL-12 production is decreased, IL-23 production is in- differentiation (53–56) (Fig. 2). Interestingly, some of these factors creased in tumors (61). Administration of PGE2 resulted in are transcriptionally regulated by IL-17, thus creating positive feed- higher expression of IL-23 and Th17 cells in the inflamed tis- by guest on September 30, 2021 back regulation of Th17 differentiation. sue. PGE2 inhibits the induction of IL-12 and IL-27, which induce IFN-␥ but inhibit IL-17 production from T cells (62). Regulation of Th17 differentiation in tumors PGE2, inducing and working with IL-23, favors the expansion It has become clear that IL-17-roducing Th17 cells and Treg of human Th17 cells and enhances IL-23-induced IL-17 pro- cells share a common pathway. Although TGF-␤ favors differ- duction by memory T cells (56). Belonging to the IL-12 family, entiation of naive T cells into Tregs, simultaneous presence of IL-23 performs protumor functions. In contrast to the antitu- both TGF-␤ and IL-6 promotes the differentiation of Th17 mor role of IL-12, IL-23 up-regulates inflammatory processes, cells. Given the tight association of TGF-␤ and IL-6 with tu- including matrix metalloproteinase expression and angiogene- mor incidence and progression, naive T cells entering an estab- sis, and reduces infiltration and function of CTLs (63), thus lished tumor are more likely to be exposed to conditions favor- contributing to tumor growth. Indeed, the IL-23/p19-deficient ing Th17 differentiation. TGF-␤ favors tumor growth by mice are completely resistant to carcinogen-induced tumors (63). The absence of tumor formation in these mice correlated with the absence of various markers that are indicative of tumor-associated inflammation, confirming the role of IL-23 and IL-17 in tumor-promoting inflammation. In fact, IL-23

Table II. List of identified tumor type with IL-17ϩ or Th17 infiltrating cells

Cancer Type Refs.

Prostate cancer 33, 42–44 Breast cancer 36, 45 ϩ Myeloma 39 FIGURE 1. Differentiation and stabilization of Th17 cells. Naive CD4 T ␤ Melanoma 46 cells activated in the presence of TGF- and IL-6 initiate the Th17 differenti- Ovarian cancer 35, 38, 47 ation characterized by expression of the cytokines IL-17 and IL-21 and the tran- Renal cell carcinoma 37 scription factor ROR␥t. IL-21 produced by Th17 cells further amplifies Th17 Colon cancer 40, 49, 50 generation in an autocrine manner. In addition, IL-21 induces the IL-23 re- Acute myeloid leukemia 41 ceptor expression on Th17 cells to make them responsive to IL-23 stimulation. Gastric cancer 34 DC-produced IL-23 stabilizes the Th17 phenotype and helps Th17 cells ac- Lymphoma 32, 48 quire effector functions. ROR-␥t induction is dependent on STAT-3, which is Pancreatic cancer 51 preferentially activated by IL-6, IL-21, and IL-23. Lung cancer 52 The Journal of Immunology 4171

production of IL-6 during Th17 polarization and revealing distinct costimulatory requirements for Th1 vs Th17 generation (72). It has been shown in an EAE model that strong antigenic stimulation of T cells up-regulated CD154 expression, which, in concert with certain microbial stimuli (i.e., cytosine phos- phate guanine, curdlan, and zymosan), synergistically increased DC IL-6 production and Th17 polarization. CD40 deficiency reduced the cytokine release, impaired Th17 development, and substantially reduced EAE. Thus, CD40-CD40L cross-talk is important for Th17 development by translating strong TCR and microbial stimuli into IL-6 production (73). Considering the above observations in different models of infection and au- toimmunity, it is possible that in a growing tumor, MHC class II and CD40 expression may be low (74) due to the prevalence of IL-4 and IL-10. IL-10 inhibits CD40 signaling as well. Ex- pression of both IL-23 and IL-6 together may be reduced to lower Th17 differentiation in tumors, but the same process pro-

vide an intratumoral TGF-␤-rich milieu that skews the Treg/ Downloaded from Th17 reciprocity toward Treg dominance.

FIGURE 2. Paradoxes in the antitumor functions of Th17. Initial infiltration Reciprocity between Treg and Th17 and the functional plasticity of the of immune cells into the tumor mass results in TNF-␣ production and activation of ϩ CD4 T cells the local and newly recruited APCs, inducing TGF-␤, IL-6, IL-23, IL-12, and IL-

10. TGF-␤ alone induces regulatory T cells (iTr), which are anti-inflammatory, but Although a predominant TGF-␤ production in tumors causes http://www.jimmunol.org/ the same cytokine with IL-6 induces IL-17-secreting Th17 cells, which are proin- Treg differentiation, the addition of IL-6 shifts the Th differ- flammatory. Although IL-23 stabilizes, iTr and IL-10 inhibit Th17 cells. On one entiation to Th17 cells, identifying IL-6 as a crucial factor in hand, PGE2 supports Th17 cells and, on the other, promotes Th2 differentiation, which is possibly triggered by the NK1.1ϩ T cell-secreted IL-4. Th2 cells secrete determining the Treg/Th17 reciprocity. Recent observations suggest that IL-2, which promotes Treg expansion, inhibits the IL-4 and inhibit Th17 cells. Thus, PGE2 seems to play dual roles by promoting both inflammatory Th17 and the counteracting Th2 cells. Th17 cells induce in- generation of Th17 cells (75). Conversely, mice lacking IL-2 or flammation in the tumor so that the T cells and other infiltrating cells destroy the STAT-5, which is required for IL-2R signaling, had fewer Tregs tumor. Paradoxically, IL-17 induces angiogenesis that helps the tumor cells metas- but more Th17 cells. Retinoic acid metabolite, secreted by DCs tasize. Thus, multiple factors act in concert, some synergistically and some coun- in tumors, can reduce Th17 but not Th1 cell differentiation by guest on September 30, 2021 teractively, to regulate the Th17-mediated control of tumor growth or regression. through the inhibition of IL-6 signaling and promote Treg cell Perhaps the conditioning of the respective cell types involved in the response and ␤ their temporal regulation are crucial to this control. generation by enhancing TGF- -induced Foxp3 promoter activity (76). Foxp3 can bind to ROR-␥t and ROR-␣ to regulate each other’s activity counteractively (77). Conditional deletion promotes the production of IL-17 by activated T cells (64). of Foxp3 recovered ROR-␥t activity and Th17 differentiation. IL-23 is not required for triggering Th17 differentiation but is Even though Foxp3 alone inhibits IL-17 expression, recent crucial for the function, survival, and propagation of this T cell studies suggest that there exists a functional plasticity between population in the inflamed environment. In contrast to the pro- these two cell types (reviewed in Refs. 78 and 79). The differ- tumor functions of IL-23, several reports have described the an- entiated Treg cells can be converted into Th17 cells under the titumor effects of IL-23. IL-23-overexpressing tumors show re- influence of strong inflammatory conditions. It has been shown duced growth and metastasis (65–69). The antitumor effects of that under IL-6 and TCR stimulation, Tregs from both the thy- IL-23 in these studies were found to be mediated through the mus and the periphery that down-regulated Foxp3 are con- ϩ enhancement of CD8 T cell response. In addition, intratu- verted to Th17 cells (80). STAT3-deficient T cells failed to moral injection of IL-23-overexpressing dendritic cells (DCs) repress Foxp3 upon IL-6 stimulation, consistent with the re- resulted in a similar phenotype (70). Artificial overexpression of quirement for STAT3 suppression of Foxp3 in developing IL-23 induced potent antitumor immunity through various Th17 cells (81). Moreover, adoptive transfer of Tregs into lym- mechanisms. For example, IL-23 can mediate myeloid infiltra- phopenic hosts resulted in the loss of Foxp3 expression, and the tion consisting of DCs, macrophages, and granulocytes, which Foxp3-negative cells could produce strong proinflammatory ϩ contribute to the inhibition of tumor growth and boost an im- cytokines including IL-17 and IFN-␥. In addition, Foxp3 IL- ϩ ϩ mune reaction to these immune-sensitive tumors. In addition, 17 CD4 T cells have been observed both in vitro, after po- IL-23 overexpression is likely to increase systemic IL-23 levels, larization in the presence of TGF-␤ and IL-6, and in vivo in ϩ ϩ ϩ leading to the growth and survival of CD8 memory T cells. mice (82, 83). Circulating human Foxp3 IL-17 T cells have IL-23 can be induced in Propionibacterium acnes-condi- in vitro suppressive activity (83). Although the origin and func- tioned dendritic cells upon re-stimulation with CD154 (71). In tion of these coexpressors are currently unknown, it is possible a model of the P. acnes infection, CD40-deficient animals had that these cells are in transition during early Treg or Th17 dif- impaired IL-17 but not IFN-␥ response. The CD40 stimula- ferentiation. Accumulating evidence has demonstrated that Tregs tion was instrumental in inducing IL-23 and IL-6, of which the exist in markedly higher proportions within PBMCs, tumor drain- latter alone proved essential for Th17 differentiation, delineat- ing lymph nodes, and tumor-infiltrating lymphocytes of patients ing sequential requirements for DC expression of CD40 and with cancer (84). Although Tregs represent the largest population 4172 BRIEF REVIEWS: IL-17 AND CANCER Downloaded from http://www.jimmunol.org/

FIGURE 3. Protumor vs antitumor functions of IL-17. A, Protumor functions of IL-17. IL-17 signaling induces the production of both proangiogenic and protumor factors from fibroblasts. IL-17 induces VEGF, which in turn induces TGF-␤ and, thereby, VEGF-mediated angiogenesis. TGF-␤ enhances the VEGF receptivity by increasing VEGF receptor expression. IL-17 also induces IL-6 expression in fibroblasts. Although IL-17-mediated IL-6 expression is regulated primarily by NF-␬B, the same cytokine can further stimulate NF-␬B-mediated transcription of its own. The increased production of IL-6 and TGF-␤ further amplifies Th17 differentiation and creates a sustained chronic inflammatory state that can favor tumor growth and metastasis. B, Antitumor functions of IL-17. Dendritic cells acquire, process tumor-associated or tumor Ags, and present epitopes to both CD4ϩ and CD8ϩ T cells, leading to differentiation of Th17 cells and effector CTLs. The differentiated Th17 cells can have multiple by guest on September 30, 2021 antitumor functions. Th17 cells potentiate effector functions of both CTLs and innate effectors such as NK cells and neutrophils. Th17 cells stimulate the secretion of IL-12 from macrophages that leads to CTL activation. Th17 cells also regulate DC maturation and effective T cell priming.

ϩ of CD4 T cells in progressing tumors, IL-17-positive T cells ac- primarily to the proangiogenic activity of IL-17. Moreover, the lev- cumulate in parallel with Tregs within tumor tissues in mice as well els of Th17 cells were positively correlated with microvessel density as in blood and ascites of various tumor tissues, and both popula- in tumors (87). By acting on stromal cells and fibroblasts, IL-17 tions reached maximal levels in advanced tumors (75). Thus, the induces a wide range of angiogenic mediators (88, 89), including conversion of Treg cells into a IL-17-producing phenotype in the vascular endothelial growth factor (VEGF), that markedly protumor microenvironment may further amplify inflammation as mote inflammatory and tumor angiogenesis (90). IL-17 is able to they control active immune responses against tumors. All of these up-regulate VEGF production by fibroblasts and therefore pro- observations suggest that in the tumor microenvironment, the reg- mote fibroblast-induced new vessel formation in inflammation ulation of Treg and Th17 proportion dictates the growth or regres- and tumors. The IL-17-VEGF loop that modulates angiogenesis sion of tumors. However, Th17 cells themselves contribute to the includes another angiogenic factor, TGF-␤. Many cancer cells ex- paradox, because part of their activities can both promote and repress high levels of TGF-␤, which seems to enhance cancer growth gress tumors. and metastasis by stimulating angiogenesis. IL-17 induces VEGF, which in turn induces TGF-␤ and, thereby, VEGF-mediated an- The paradox of the protumor and antitumor functions of IL-17 giogenesis (91). TGF-␤ enhances the VEGF receptivity of endo- Protumor functions of IL-17. Many functions of IL-17 in the tu- thelial cells by increasing VEGF receptor expression (92). IL-17 mor microenvironment contribute to tumor progression. Apart also induces IL-6 and PGE2 and enhances ICAM-1 expression in from a minor direct effect on the proliferation and survival of tu- fibroblasts. All of these molecules were known to have a major role mor cells (34), as not all tumor cells express IL-17 receptor and in angiogenesis and tumor invasion (Fig. 3). IL-17 appears to stim- respond to IL-17, the major protumor role of IL-17 in inflamma- ulate production of IL-8 (93). IL-8 signaling promotes angiogenic tion-associated cancer relies on its proangiogenic property of sur- responses in endothelial cells, increases proliferation and survival of rounding endothelial cells and fibroblasts. For example, IL-17- endothelial and cancer cells, and potentiates the migration of can- overexpressing human cervical cancer cells and nonsmall cell lung cer cells and infiltrating neutrophils at the tumor site. Accordingly, carcinoma cells show greater ability to form tumors in immuno- IL-8 expression correlates with the angiogenesis, tumorigenicity, compromised mice compared with control cells not overexpressing and metastasis of tumors in numerous xenograft and orthotopic in IL-17 (85, 86). In addition, IL-17 overexpression in fibrosarcoma vivo models (94). Moreover, IL-17 was found to induce IL-1␤ and cells enhances their tumorigenic growth in syngenic mice, owing TNF-␣ in macrophages, and these cytokines can further synergize The Journal of Immunology 4173 with IL-17 to activate neutrophil-specific chemokines, thereby re- the induction of tumor-specific CTL induction. IL-17 pro- cruiting neutrophils to the site of inflammation (95). motes the maturation of DC progenitors as indicated by in- Recently, the transcription factor NF-␬B has been identified creased expressions of costimulatory molecules, MHC class II as a potential molecular bridge between inflammation and can- Ags, and allostimulatory capacity (109). This may lead to fur- cer (96). However, IL-17R signaling via ERK1, ERK2, JNK, ther improvement in T cell priming by tumor cells producing and p38 MAPKs results in the activation of NF-␬B, albeit IL-17 (Fig. 3). In addition, IL-17-transduced fibrosarcoma cells weakly (97–100). Although proinflammatory cytokines (e.g., induced tumor-specific antitumor immunity by augmenting ␣ IL-6 and TNF- ), chemokines (e.g., IL-8), PGE2, matrix met- the expression of MHC class I and class II Ags (110). These alloproteinase, and several adhesion molecules are reported to studies were focused on the effects of exogenous IL-17 in estab- require NF-␬B-mediated transcriptional activation (reviewed lished mouse tumor cell lines. A recent demonstration shows in Refs. 24 and 101), the role of the same transcription factor in that tumor growth in subcutaneous tissue and lung tumor me- the IL-17-mediated inflammatory responses remain to be estab- tastasis are enhanced in IL-17-deficient mice. The effect is ac- lished. Although IL-17-mediated cytokine expression is regu- companied by reduced IFN-␥ levels in tumor-infiltrating NK lated primarily by NF-␬B, the same cytokines can further stim- cells and T cells (111). Although this study emphasizes the im- ulate NF-␬B-mediated transcription of their own in tumor cells portance of endogenous IL-17 in tumor immunity in one par- and tumor-associated stromal cells, thereby creating a sustained ticular model, it remains to be determined whether endogenous chronic inflammatory state within the tumor microenviron- IL-17 is involved in regulating tumor immunity in other tumor ment (Fig. 3). In support of this notion, enhanced cervical can- models, and the involvement of other Th17-associated mole- Downloaded from cer growth elicited by IL-17 was associated with increased ex- cules such as IL-17F and IL-22 in determining tumor growth pression of IL-6 and macrophage recruitment to the tumor sites must also be studied. Although IL-17 has been shown to pro- (86). Therefore, IL-17 might also function through IL-6 to promote tumor growth by inducing angiogenesis, the same process mote tumor development. provides the channel through which the immune cells can in- Chemokines can stimulate or inhibit proliferation and che- vade and inflict an assault on the relatively inaccessible tumor motaxis of endothelial cells of the blood vessels that serves tu- cells at the core of the solid tumor mass. Thus, IL-17-induced http://www.jimmunol.org/ mors. The balance between angiogenic and angiostatic chemo- angiogenesis might also promote antitumor immunity by being kines in the tumor microenvironment can determine tumor a supply channel for immune cells to reach and attack the inner survival. When a tumor or tumor-infiltrating immune cells se- mass of solid tumor. crete more of an angiogenic chemokine than an angiostatic chemokine, angiogenesis is stimulated and leads to new blood ves- Conclusions sel formation and continued tumor growth. In contrast, an IL-17 secreting Th cells, termed Th17 cells, can either stimulate or excess of angiostatic chemokines in the tumor microenviron- inhibit tumor growth and progression. Many of the inflammatory ment can inhibit neovascularization and cause the subsequent functions of IL-17 can initially benefit the host, but with the al- by guest on September 30, 2021 arrest of tumor growth (102, 103). IFN-␥ is a potent inducer of tered tumor microenvironment, IL-17 starts promoting tumor angiostatic cytokines (e.g., CXCL10) from a variety of cells, in- growth. The pro-tumor vs anti-tumor effects of IL-17 are thus cluding fibroblasts, endothelial cells, and tumor cells (104). In functions of the IL-17-induced inflammatory mediators and, per- contrast, IL-17 has been shown to selectively enhance the pro- haps, the mediators that counter-regulate IL-17 production, all op- duction of angiogenic chemokines such as CXCL1, CXCL5, erating in tandem. These factors regulate the plasticity of the T cell ϩ CXCL6, and CXCL8 in tumor cells and epithelial cells (85, differentiation—from cytotoxic CD8 T cells to IL-17-producing ϩ 105). In addition, IL-17 is also known to inhibit angiostatic inflammatory CD8 T cells or from Treg to Th17 or vice ver- chemokine secretion by fibroblasts (85). Thus, IL-17 may shift sa—by reprogramming the switching of gene expressions in T cells the local biologic balance between angiogenic and angiostatic (112–114). Therefore, to formulate a more efficient therapeutic chemokines toward a predominance of angiogenic chemokines strategy, we need to better understand the role of the factors that to enhance the net angiogenic activity. regulate T cell plasticity. Antitumor functions of IL-17. Although IL-17 seemed to us to be a potential tumor-promoting cytokine, a sizeable number of re- Disclosures ports have described tumor-inhibitory effects of IL-17. Th17- The authors have no financial conflict of interest. polarized cells were found to be more effective than Th1 cells in eliminating large established tumors (106). However, the References Th17-mediated tumor responses were highly dependent on 1. Murugaiyan, G., S. Martin, and B. Saha. 2007. CD40-induced countercurrent con- IFN-␥. Indeed, the effects of Th17-polarized cells were com- duits for tumor escape or elimination? Trends Immunol. 28: 467–473. ␥ 2. Zitvogel, L., A. Tesniere, and G. Kroemer. 2006. Cancer despite immunosurveil- pletely abrogated by the administration of IFN- -depleting Abs lance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6: 715–727. and not by IL-17- or IL-23-depleting Abs. The Th17-polarized 3. Wang, H. Y., and R. F. Wang. 2007. Regulatory T cells and cancer. Curr. Opin. Immunol. 19: 217–223. cells also secreted cytokines associated with the Th17 pheno- 4. Murugaiyan, G., S. Basak, and B. Saha. 2006. 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