UBC Faculty Research and Publications

Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis Marshall, Erin A; Ng, Kevin W; Kung, Sonia H Y; Conway, Emma M; Martinez, Victor D; Halvorsen, Elizabeth C; Rowbotham, David A; Vucic, Emily A; Plumb, Adam W; Becker-Santos, Daiana D; Enfield, Katey S S; Kennett, Jennifer Y; Bennewith, Kevin L; Lockwood, William W; Lam, Stephen; English, John C; Abraham, Ninan; Lam, Wan L Oct 27, 2016

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REVIEW Open AccessEmerging roles of T helper 17 andregulatory T cells in lung cancerprogression and metastasisErin A. Marshall1†, Kevin W. Ng1†, Sonia H. Y. Kung1,5*†, Emma M. Conway1,2, Victor D. Martinez1,2,Elizabeth C. Halvorsen1, David A. Rowbotham1, Emily A. Vucic1,2, Adam W. Plumb3,4, Daiana D. Becker-Santos1,Katey S. S. Enfield1, Jennifer Y. Kennett1, Kevin L. Bennewith1,2, William W. Lockwood1,2, Stephen Lam1,John C. English2, Ninan Abraham3 and Wan L. Lam1,2,5*AbstractLung cancer is a leading cause of cancer-related deaths worldwide. Lung cancer risk factors, including smoking andexposure to environmental carcinogens, have been linked to chronic inflammation. An integral feature of inflammationis the activation, expansion and infiltration of diverse immune cell types, including CD4+ T cells. Within this T cellsubset are immunosuppressive regulatory T (Treg) cells and pro-inflammatory T helper 17 (Th17) cells that act in a finebalance to regulate appropriate adaptive immune responses.In the context of lung cancer, evidence suggests that Tregs promote metastasis and metastatic tumor focidevelopment. Additionally, Th17 cells have been shown to be an integral component of the inflammatorymilieu in the tumor microenvironment, and potentially involved in promoting distinct lung tumor phenotypes.Studies have shown that the composition of Tregs and Th17 cells are altered in the tumor microenvironment,and that these two CD4+ T cell subsets play active roles in promoting lung cancer progression and metastasis.We review current knowledge on the influence of Treg and Th17 cells on lung cancer tumorigenesis, progression,metastasis and prognosis. Furthermore, we discuss the potential biological and clinical implications of the balanceamong Treg/Th17 cells in the context of the lung tumor microenvironment and highlight the potential prognosticfunction and relationship to metastasis in lung cancer.Keywords: Th17, IL-17, Regulatory T cell, Treg, Lung cancer, Inflammation, Cancer immunology, Tumormicroenvironment, Tumorigenesis, PrognosisBackgroundLung cancerLung cancer is the leading cause of cancer-related deathsworldwide, with a dismal five-year survival rate of 17 %[1, 2]. There are two major types of lung cancer: small-cell lung cancer (SCLC), which accounts for ~15 % oflung cancer patients, and non-small-cell lung cancer(NSCLC), comprising the remaining ~85 % [3] (Fig. 1).The three major histological subtypes of NSCLC areadenocarcinoma (AC), squamous cell carcinoma (SqCC)and large cell carcinoma (LCC) (Fig. 1). AC is the mostcommon histological subtype of lung cancer, accountingfor approximately half of NSCLC cases (43.3 %; SEERCancer Statistics Review, 1975–2012) and typically arisesin the glandular epithelium of the lung periphery fromeither bronchioalveolar stem cells, club (formerly Clara)cells or type II pneumocytes [3–5] (Fig. 1). AC is alsothe predominant subtype that arises in patients whohave never smoked [6]. By contrast, SqCC accounts forapproximately 30 % of NSCLC (22.6 %; SEER CancerStatistics Review, 1975–2012), develops primarily in thecentral airways and segmental bronchi, and strongly asso-ciates with a history of smoking [3, 5, 7] (Fig. 1). RegardingSCLC, the cell of origin has yet to be defined, but has beenpostulated to originate from differentiated neuroendocrine* Correspondence: skung@bccrc.ca; wanlam@bccrc.ca†Equal contributors1Department of Integrative Oncology, British Columbia Cancer Agency,Vancouver, CanadaFull list of author information is available at the end of the article© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Marshall et al. Molecular Cancer  (2016) 15:67 DOI 10.1186/s12943-016-0551-1cell lineages, committed neuroendocrine progenitor cellsor non-neuroendocrine cells that acquire neuroendocrinedifferentiation in the lung [8, 9] (Fig. 1).Inflammation and lung cancerInflammation has been shown to promote cancer initi-ation and progression [10]. Specifically, inflammatoryprograms have been implicated in all aspects of cancerdevelopment, including malignant transformation, cellproliferation and survival, angiogenesis, invasion andmetastasis [11]. Studies have indicated a strong relation-ship between lung cancer risk factors and alterations ininflammatory cytokine levels, oxidative stress markersand immune cell composition.Lung cancer risk factors, inflammatory cytokines andoxidative stressExposure to tobacco smoke is a principal risk factor as-sociated with lung cancer — smokers display a 14-foldincreased risk of developing lung cancer compared tonever smokers [12]. Although lung cancer is oftenviewed as a smoker’s disease, if lung cancer in neversmokers was considered as its own disease, it wouldrank as the seventh most common cause of cancerdeaths worldwide and account for 300,000 deaths eachyear [6]. Other factors known to influence lung cancerrisk include environmental carcinogens such as arsenic,radon, asbestos, air pollution, viral infection and geneticrisk factors, including a family history of lung cancer[6, 13–16]. Furthermore, individuals with inflammatorylung disease, such as chronic obstructive pulmonary dis-ease (COPD), have an elevated risk of developing lungcancer [17].Cigarette smoking is known to drive altered local andsystemic levels of inflammatory cytokines and reactiveoxygen species (ROS) in the development of smoking re-lated lung cancers. For example, inflammatory markers,including C-reactive protein (CRP), chemokine (C-Cmotif ) ligand (CCL) 17, and CCL22, are elevated in theserum of former or current smokers compared to neversmokers [18]. Furthermore, elevated levels of circulatinginflammatory molecules CRP, CCL22, CCL17 and alsochemokine (C-X-C motif ) ligand (CXCL) 5, CXCL7,CXCL9, CXCL13 are associated with increased lung can-cer risk in both current and former smokers [19].Smokers with lung cancer have increased serum CCL20levels, an inflammatory molecule shown to promotetumor cell proliferation and migration, that has alsoFig. 1 Percent incidence and typical histologies of lung cancer subtypes. Percent incidences shown are specific to American populations [5].Locations of lung cancers depicted are generalized sites typical of lung tumorigenesis for subtypes. Lung cancers are classified into two majortypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). All forms of pulmonary carcinomas may be distributed throughoutthe lung but some locations are more typical for certain classes. SCLC primarily originates from central airways, and neuroendocrine cells arethought to be the precursors of this tumor type. As a heterogeneous disease, NSCLC is further subdivided into three major subtypes: squamouscell carcinoma (SqCC), large cell carcinoma (LCC) and adenocarcinoma (AC). Percentage distributions of NSCLC histologies total to NSCLC percentage(83.4 %), where remaining histogies (non-small cell carcinoma and other specified carcinomas) are not depicted. SqCC predominately originates fromcentral airways and segmental bronchi and are thought to arise from basal cells. LCC are classified as tumors without general features associated withSCLC, SqCC and AC and may arise anywhere in the lung. The most common type of NSCLC is AC and is thought to principally arise fromtype II pneumocytes and club cellsMarshall et al. Molecular Cancer  (2016) 15:67 Page 2 of 15been significantly correlated with advanced disease andpoor prognosis in lung cancer [20]. Surfactant protein D(SFTPD) is an important regulator of innate immunity,inflammation and oxidative stress secreted by type IIpneumocytes in the airway; decreased expression of thisprotein in bronchoalveolar lavage (BAL) of smokers cor-relates with progression of bronchial dysplasia [21]. Inaddition to inflammatory cytokines and chemokines,ROS is also a major mediator of smoke induced damage,chronic inflammation and cancer development by pro-moting oxidative DNA damage and genomic instability[22]. Cigarette smoke is an enriched source of oxidants,which can enhance ROS generation by phagocytes topromote oxidative stress [23]. Increased recruitment ofthese phagocytes, including neutrophils and macrophages,is prominent in the lungs of smokers and patients withCOPD compared to non-smokers [23]. Alternative oxida-tive stress markers, like extracellular superoxide dismutase(ECSOD), are elevated in the sputum of smokers [23, 24].Taken together, alterations in cytokine and oxidative stressprofiles of smokers indicate the presence of an importantmolecular link between smoking and lung inflammation.In addition to smoking, exposure to airborne irritantsand environmental carcinogens has been shown to in-duce lung inflammation. A well-documented example isasbestos, which refers to six unique silicate mineral fi-bers: chrysotile, amosite, crocidolite, tremolite, antho-phyllite and actinolite. Inhaled asbestos fibers largerthan 20 μm are not efficiently phagocytosed and remainin lung tissue, where they induce fibrosis, inflammationand eventually, carcinogenesis [15, 25]. Most of the in-flammation driven effects of asbestos exposure are a con-sequence of increased ROS production [26]. The presenceof asbestos fibers induces a chronic inflammatory re-sponse, which generates significant ROS that contributesto subsequent DNA damage [26, 27]. Interestingly, differ-ent classes of asbestos fibers can induce changes in cyto-kines detectable in the serum, including cytokinescharacteristic of a T helper 17 (Th17) immune response,which will be discussed further below. In mice, intratra-cheal exposure to chrysotile asbestos induces a pattern ofchronic inflammation associated with Th1 cytokines, whileamphibole asbestos exposure induces both a Th1 andTh17 cytokine response [28]. Additionally, it has beenshown that tremolite and erionite (a fiber with similarcharacteristics to amphibole asbestos) exposure causedincreased IL-17 in splenocyte cultures, and erionite expos-ure induced elevated serum IL-17 levels in mice [29].Finally, respiratory diseases involving chronic inflam-mation are linked with lung cancer risk. Of note, pa-tients with the inflammatory lung disease COPD haveup to a tenfold increase of lung cancer risk, and COPDis linked to activation of pro-tumorigenic inflammatorysignaling pathways in immune cells [30]. Tumor andimmune cells can communicate through nuclear factorkappa-light-chain-enhancer of activated B cells (NF-κB)and signal transducer and activator of transcription 3(STAT3)-dependent cytokine production. Oncogenicactivation of STAT3 and NF-κB induces cytokine produc-tion by tumor cells that can regulate immunosuppressiveand tumor-promoting functions of tumor infiltrating im-mune cells via trans-activation of these same transcriptionfactors [31]. This molecular pathway is noted as a poten-tial mechanism for COPD-related lung cancer develop-ment [31–33]. Taken together, these studies highlight thatlung cancer risk is influenced by changes in systemic andlocal inflammation. Moreover, altered compositions andactivities of immune cells modulate the tumor microenvir-onment to promote lung cancer development.Inflammatory cells and lung cancerThe biological process of inflammation relies on recruit-ment of diverse immune cell types. The inflammatory re-sponse depends on innate and adaptive immune cellactivities to maintain tissue homeostasis [34]. However,immune cell infiltration is observed in tumors and canalso promote cancer development, progression and metas-tasis [35] (Fig. 2). Immune cell composition in the tumormicroenvironment may contribute to immune evasionand cancer development [36]. Innate and adaptive im-mune cells, including macrophages, neutrophils, naturalkiller (NK) cells and B cells, have been implicated in bothanti-tumor and pro-tumor activities [37–43]. Specifically,the anti-tumor and pro-tumor roles of T cells in cancerdevelopment are currently of great interest. Therapeuticstrategies targeting this adaptive immune cell type havebeen a major focus of recent immunotherapy develop-ment and applications, including for lung cancertreatment [44, 45].T cells play diverse roles in the immune response andare highly relevant to lung cancer biology. CD8+ cyto-toxic T lymphocytes (CTLs) facilitate immunosurveil-lance by T cell receptor (TCR) recognition of antigensbound to major histocompatibility complex (MHC)-I onantigen presenting cells and when activated, produceinterferon gamma (IFN-γ), perforin and granzyme B thatcontribute to tumor cell cytolysis [46]. In addition toCD8+ CTLs, various CD4+ T cells, including regulatoryT (Treg) and T helper 17 (Th17) CD4+ T cell subsetshave emerged as key players across a variety of diseasesinvolving inflammation, including cancer. Both theseCD4+ T cell subsets facilitate a pro-tumor environmentthrough the promotion and maintenance of an immuno-suppressive and pro-tumor inflammation environmentthat could favor tumorigenesis, cancer progression andmetastasis. Treg and Th17 subsets are generally thoughtto play opposing roles in regulating immunity, where cellfate determineration arises from a balance of transcriptionMarshall et al. Molecular Cancer  (2016) 15:67 Page 3 of 15factors governing CD4+ T cell differentiation and Treg andTh17 cell generation [47]. For instance, mouse and humanstudies show that expression of the transcription factorforkhead box P3 (FoxP3) represses Th17 transcription fac-tors retinoic acid receptor-related orphan receptor gammat (RORγt) and ROR alpha (RORα) to drive Treg differenti-ation [48, 49]. Moreover, Th17 differentiation can occurwhen pro-inflammatory cytokines, including IL-6, IL-21and IL-23, inhibit FoxP3 expression and subsequent repres-sion of RORγt [48, 50]. In addition to de novo generationof Tregs from FoxP3− T cells, Tregs can also be generatedunder homeostatic or pathological conditions via prolifera-tion of thymus-derived FoxP3+ cells [51, 52]. Additionally,a novel mechanism of Treg-dependent promotion of Th17differentiation via IL-2 sequestration has been shown topromote IL-17-driven inflammation and tumorigenesis incolon cancer, highlighting the complex interplay betweenthese two cell types in the context of cancer [53].Main textTregs and lung cancerBy maintaining tolerance toward innocuous antigens,Tregs represent a vital component of the adaptive im-mune system, which functions to prevent autoimmunityand chronic inflammation [54, 55]. Tregs represent aphenotypically diverse cell lineage classified according totheir site of differentiation, either in the thymus or atextrathymic sites [56]. Although not definitive, thesecells are generally characterized as CD4+CD25high, andexpress the master regulatory transcription factor FoxP3[57]. Tregs can induce immunosuppression throughcontact-dependent mechanisms such as the expressionof cytotoxic T-lymphocyte-associated protein 4 (CTLA-4),programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), lymphocyte-activation protein 3 (LAG-3),CD39/73 and neuropilin 1 (Nrp1), or through contact-independent mechanisms, including the sequestration ofFig. 2 Variable immune cell infiltration within pulmonary AC in patients. a Lepidic growth pattern showing wide expansion (star) of alveolarinterstitium by a diffuse population of mononuclear inflammatory cells, principally lymphocytes. Arrow indicates neoplastic cells. b A similartumor showing minimal interstitial expansion (star) with few infiltrating inflammatory cells. Arrow indicates neoplastic cells. c Another lepidicgrowth region of AC showing focal expansion of the interstitium by lymphoid follicular hyperplasia (star). Arrow indicates neoplastic cells. d ACwith infiltrating acinar pattern showing a desmoplastic (fibroblastic scarring) reaction (star) with very few infiltrating lymphocytes. Arrow indicatesneoplastic cells. e AC with a papillary pattern demonstrating alveolar septae (arrow heads) with no fibrous expansion and no infiltration bylymphocytes. Arrow indicates neoplastic cells. Original magnification for images 100xMarshall et al. Molecular Cancer  (2016) 15:67 Page 4 of 15IL-2 and the production of the soluble immunosuppressivemolecules IL-10, TGF-β, adenosine, prostaglandin E2(PGE2) or galectin-1 [52, 55, 58–61] (Fig. 3a). In carcino-genesis, systemic expansion and intratumoral accumulationof immunosuppressive Tregs is thought to disrupt anti-tumor immunity, leading to the growth and metastasis of avariety of malignancies, including lung, breast, prostate andovary [54, 56]. Certain cell surface molecules have beenshown to have stabilizing effects on the Treg cellpopulation: CD39 (ectonucleoside triphosphate dispho-sphohydrolase 1; ENTPD1) has been shown to increasestability of CD4+ FoxP3+ Tregs, contributing to their im-munosuppressive function [62]. By suppressing anti-tumoreffector cells, Tregs have emerged as active contributors tocancer progression [63, 64].Tregs are implicated in the early stages of tumor de-velopment. In murine models of mutant Kras-drivenAC, tumorigenesis was found to be Treg dependent,Fig. 3 Potential roles of Tregs associated with lung cancer development. a Contact-dependent and contact-independent mechanisms of Tregs inmediating tumorigenesis. All receptors shown are mouse specific. For humans, receptors shown are human-specific except for LAG3, CD73 andNrp1, which are non-human specific or where human specificity remains undetermined. b Immunosuppressive and pro-tumorigenic processes inlung cancer development depend on quantitative relationships of Treg populations. Arrows indicate Treg-dependent processes, with red indicatingpositive relationships and blue indicating negative Treg-dependent relationshipsMarshall et al. Molecular Cancer  (2016) 15:67 Page 5 of 15with Kras transgenic mice deficient in FoxP3+ Tregs de-veloping 75 % fewer lung tumors [65] (Fig. 3b). Tobaccocarcinogen exposure increased pulmonary FoxP3+ lym-phocytes prior to tumor development, suggesting a po-tential role for Tregs in the generation of a favorableniche for the development of lung tumors driven byKras, mutations mainly found in smoker-related lungcancers [65].Tregs influence the tumor microenvironment duringthe progression of lung cancers. Murine models of lungAC have demonstrated that Tregs may inhibit CD8+ Tcell-mediated anti-tumor immunity (Fig. 3b), with thedepletion of Tregs resulting in tumor cell death and ele-vated levels of granzyme A, granzyme B, perforin andIFN-γ in infiltrating CD8+ T cells at early stages oftumorigenesis [66]. Further, the development of SCLCinfluences immunosuppressive activities of Tregs, whereSCLC cell lines were reported to induce Treg generationfrom CD4+ T cells through the production of IL-15 [67](Fig. 3b). In lung tumors, Tregs are also associated withexpression of angiogenic and metastatic potentiatorcyclooxygenase-2 (COX2), where elevated numbers ofintratumoral FoxP3+ lymphocytes were positively corre-lated with high intratumoral expression of COX2, andcan be induced by the tobacco carcinogen nicotine-derived nitrosamine ketone (NNK) in mouse lungs[68, 69] (Fig. 3b).Emerging evidence suggests that Tregs promote me-tastasis and metastatic tumor foci development [52]. Aclinical study of NSCLC observed that Treg levels inperipheral blood increased with stage and were highestin patients with metastatic tumors [70]. It was also re-ported that Treg levels were elevated in metastaticlymph nodes compared to nonmetastatic lymph nodesin patients with AC [71, 72]. Mouse models of Lewislung carcinoma reveal that Tregs inhibit NK cell-mediated cytotoxicity in a TGF-β-dependent manner,and that depletion of Tregs contributes to enhanced NKcell antimetastatic activities [73] (Fig. 3b). Prognostically,the relative accumulation of Tregs in NSCLC tumors,and peripheral blood of SCLC patients (in relation to ef-fector T cell populations) has been linked to increasedrisk of recurrence, and a high proportion of FoxP3+ lym-phocytes in SCLC lung tumor biopsies correlates withpoor survival [67, 68, 74, 75]. Another study in NSCLCidentified elevated levels of intratumoral FoxP3+ lym-phocytes were associated with reduced recurrence-freesurvival [68].Taken together, these findings underscore the rele-vance of Tregs in promoting lung cancer progressionand metastasis. In a clinical setting, targeting the im-mune checkpoint molecules CTLA-4 and PD-1 have re-cently received much attention in a variety of cancertypes including lung cancers [76–79]. Ligation of thesereceptors leads to inhibition of T cell activation, particu-larly that of effector CD8+ T cells. The anti-CTLA-4 im-munotherapeutic agent ipilimumab has demonstratedpromising results in improving SCLC and NSCLC pa-tient outcomes, while nivolumab (anti-PD-1 therapy) hasbeen approved by the Food and Drug Administration(FDA) for the treatment of advanced squamous andnon-squamous NSCLC [76–80]. However, the responserate to nivolumab was only 20 % in lung SqCC patients,and determining clinical biomarkers for treatment strati-fication for these available immunotherapies is a majorfocus [78, 81]. Currently, clinical biomarkers are limitedfor these treatments, as patients with little to no expres-sion of these molecules in their lung tumors can stillhave beneficial therapeutic responses. For instance, pa-tients harboring tumors with negative expression of thePD-1 ligand, PD-L1, can also benefit from anti-PD1/PD-L1 therapies, suggesting that clinical use of PD-L1 posi-tivity as selection criteria could exclude patients whocould potentially benefit from these treatments [61].Other factors are at play and the molecular mechanismsunderlying Treg recruitment and their immunosuppres-sive functions in the lung tumor microenvironmentrequire further study to improve patient therapy andoutcomes.Th17 cells and lung cancerTh17 cells are a group of CD4+ T helper cells that arephenotypically distinct from Th1 and Th2 cells, andhave been characterized in many inflammatory lung dis-eases, including COPD [82–89]. Th17 cells express thetranscription factors RORγt/RORC2 (mouse/human)and RORα, which drive Th17 differentiation and pro-duce pro-inflammatory cytokines, including IL-17A, thatmodulate the tumor microenvironment [90, 91] (Fig. 4).The IL-17 cytokine family contributes to inflammation,cytokine and chemokine production, neutrophil recruit-ment in the context of lung inflammation and infection,and lung antitumor immunity [92, 93] (Fig. 4). Alter-ations to IL-17 and its signaling pathways are relevant tolung cancer development with IL-17 polymorphisms andepigenetic changes to the IL-17 signaling pathway cor-relating with increased predisposition to lung cancers[89, 94]. Thus, Th17 cells are an integral component ofthe inflammatory milieu in the tumor microenviron-ment, and may be causally involved in promoting dis-tinct lung tumor phenotypes.The IL-17 family of cytokines is comprised of sixmembers: IL-17A (also known as IL-17), IL-17B, IL-17C,IL-17D, IL-17E (also called IL-25) and IL-17 F [93, 95].Th17 cells produce IL-17A and IL-17 F [93, 96]. SerumIL-17 levels strongly associate with lung cancer develop-ment. Serum IL-17 levels were found to be significantlyhigher in NSCLC compared to subjects without cancer,Marshall et al. Molecular Cancer  (2016) 15:67 Page 6 of 15which could potentially offer an additional diagnosticmarker for NSCLC [97]. IL-17 cytokines contribute toinflammation by facilitating pro-inflammatory cytokineand chemokine induction. Exogenous treatment ofmouse embryonic fibroblasts (MEFs) with either IL-17Aor IL-17 F induced greater expression of IL-6, CXCL1,CCL2 and CCL7. Elevated expression of chemokinesCCL7, CCL22, CCL20, CCL11 and chemokine (C-X3-Cmotif ) ligand 1 (CX3CL1) were found in the lungs oftransgenic mice chronically overexpressing IL-17A. Inaddition to upregulating these chemokines, elevatedCCL1, CCL2 and CXCL1 expression was also present inthe mouse lung epithelial cell line MLE12 upon exogen-ous IL-17A treatment [98] (Fig. 4).Genetic variation and epigenetic alterations to the IL-17 F pathway may impact lung cancer development. Epi-genetic analysis of DNA methylation patterns of COPDsmall airway epithelia has highlighted the relevance ofthe IL-17 F inflammatory response pathway in a diseasesignificantly linked to lung cancer [89]. Specifically inCOPD small airways, IL-17 receptor C (IL17RC) andCXCL1 (upstream and downstream components of theIL-17 F inflammatory pathway, respectively) were bothidentified to be hypermethylated and underexpressed,while DNA hypomethylation and overexpression of col-ony stimulating factor 2 (CSF2), an IL-17 F-induced pro-inflammatory cytokine, was observed [89]. Many othergenes in the IL-17 F inflammatory pathway were alsofound to be altered by DNA methylation in COPD smallairways, and alterations of these genes are known tocontribute to carcinogenesis [99] (Fig. 5, Table 1). Singlenucleotide polymorphisms (SNPs) in IL-17 F genes aresignificantly associated with lung cancer development.For example, the IL-17 F 7488G allele is associated withadvanced stage or metastatic lung cancer in a Tunisianpopulation [94]. COPD was characterized by increasedTh17 cells (CD3+CD4+IL-17A+) in peripheral blood[100]. Likewise, high levels of Th17 cell cytokines havebeen observed in BAL of mouse models bearing onco-genic Kras-driven lung AC with concurrent induction ofFig. 4 Pro-inflammatory and pro-tumorigenic roles of Th17 cells in lung cancer pathogenesis depend on Th17 cell cytokine production. Th17cells are cardinal producers of IL-17, a family of pro-inflammatory cytokines orchestrating a variety of molecular mechanisms that promotelung tumorigenesis. For specific pro-inflammatory cytokine and chemokine expression stimulated by IL-17A or -F, refer to text in Section “Th17cells and lung cancer”Marshall et al. Molecular Cancer  (2016) 15:67 Page 7 of 15COPD-like inflammation through exposure to Hae-mophilus influenzae lysate (NTHi) [101]. Il17−/− micehad reduced lung tumor numbers, as well as reducedtumor cell proliferation, angiogenesis, myeloid cell re-cruitment and expression of pro-inflammatory mediators(Il6, Cxcl2, Ccl2, Arg1, Csf3, Mmp7, Mmp12 andMmp13) compared to Il17+/+ mice (Fig. 6). Of note, reduc-tion of lung tumor numbers occurred with IL-17 defi-ciency, but not with IL-17 F deficiency in lung tumorbearing mice [101]. Similarly, IL-17 has been shown topromote tumor growth in mice by increasing angiogenesis,metastasis and macrophage infiltration into tumors [102].In malignant disease, increased expression of Th17markers (IL-17A, RORα4 and RORγt) was observed inhuman lung AC compared to non-malignant lung tissue[103]. Th17 cells are key producers of IL-17, and thiscytokine is known to contribute to the induction of lungcancer prometastatic factor expression. Elevated expres-sion of IL-17 in peripheral blood was significantly corre-lated with TNM (tumor node metastasis) stage andFig. 5 The IL-17 F signaling pathway is epigenetically altered in malignant COPD and non-malignant COPD lung airway epithelial cells. Topdisrupted downstream molecular components of the IL-17 F pathway are involved in mediating inflammatory and anti-microbial processes. Genesinvolved in IL-17A signaling pathways and that overlap with deregulations in the IL-17 F signaling pathway are also depicted. CCL2: chemokine(C-C motif) ligand 2; CXCL1: chemokine (C-X-C motif) ligand 1; G-CSF: granulocyte colony-stimulating factor 3; CX3CL1: chemokine (C-X3-C motif)ligand 1, GM-CSF: granulocyte-macrophage colony-stimulating factor; HBD1: defensin beta 1; IL: interleukin; IL-17RA: interleukin 17 receptor A;IL- 17RC: interleukin 17 receptor C; LCN2: lipocalin 2Table 1 Examples of genes in the IL-17 F pathway epigenetically altered in COPD and their respective roles in cancerEpigenetically disrupted in COPD Roles in cancer ReferencesIL-1α Tumor cell-derived IL-1α increases tumor immunogenicityPrecursor IL-1α from necrotic tumor cells promotes inflammation[155]IL-1β Polymorphisms associated with overall cancer risk [156]IL-10 Polymorphisms associated with overall cancer riskInduces IFN-γ-mediated CD8+ anti-tumor immunityTreg cell-derived IL-10 suppresses Th17 inflammation[157–159]CCL2 Promotes metastasis and angiogenesisRecruits monocytes and macrophages contributing to inflammation[160, 161]CXCL1 Promotes metastasis, angiogenesis and cell proliferationInduces constitutive NF-κB activationFacilitates tissue damage[162, 163]GM-CSF/G-CSF Promotes angiogenesisG-CSF contributes to myeloid derived suppressor cell recruitment at tumor site[164, 165]LCN2 Induces epithelial-mesenchymal transition (EMT) and promotes metastasisPromotes cell survival through iron sequesteration[166, 167]HBD1 Disrupts cell membrane and activates caspases in tumor cellsFrequently lost in cancers, including prostate and renal cancersRecruits immature dendritic cell and memory T cell[168, 169]Marshall et al. Molecular Cancer  (2016) 15:67 Page 8 of 15increased expression of IL-17 receptor (IL-17RC) inNSCLC tumor cells was associated with invasive poten-tial [104]. Treatment of NSCLC cell lines A549 andH520 with IL-17 resulted in increased phosphorylationof STAT3, which upregulated prometastatic factor pro-duction including vascular endothelial growth factor(VEGF) [105]. While IL-17 upregulation of STAT3 wasshown to be mediated by IL-6 other cancer types[106, 107], this phenomena did not hold true in thiscase [105]. As a mechanism of lymph node metastasis, IL-17 can promote lymphangiogenesis by upregulating theexpression of the lymphangiogenic factor vascular endo-thelial growth factor-C (VEGF-C) in murine lung cancercells [108, 109] (Fig. 4). In humans, increased density ofIL-17 positive cells in NSCLC tumors correlated withlymphatic vessel density [110]. Furthermore, loss of IL-17has been shown to reduce metastases. Studies have shownthat when challenged with Lewis lung carcinomacells, IL-17 knockout mice had reduced number ofmetastatic nodules in lungs and improved survivalFig. 6 Treg/Th17 ratios are context-dependent in lung cancer patients and associate with disease pathogenesis and outcome of lung cancers.Blue arrows indicate negative relationships, and red arrows indicate positive relationships. Balance beams indicate correlation among Treg andTh17 cell subsets, with intermediate IL-17+FoxP3+ phenotypes present at the centre to indicate that these cells may contribute to cell ratios. TheTreg/Th17 ratio has been primarily assessed in pleural effusion and peripheral blood in malignant and non-malignant pleural effusions. MPE:malignant pleural effusion; NMPE: non-malignant pleural effusion derived from non-chronic diseases; PPE: parapneumonic effusion; TPE: Tuberculouspleural effusionMarshall et al. Molecular Cancer  (2016) 15:67 Page 9 of 15compared to wild-type mice [104, 111]. Taken together,these studies reveal potential mechanistic and functionaleffects of IL-17 in cancer progression and metastasis.Th17 cells produce other cytokines in addition to IL-17,including IL-22, which is also associated with lung cancer.IL-22 contributes to pro-survival signaling, angiogenesisand metastasis, part of which may be associated with its ac-tivation of STAT3 signaling pathway in cancer cells [112](Fig. 4). High levels of IL-22 have been detected both locallyin primary tumors and malignant pleural effusions (MPEs)and systemically in serum of NSCLC patients [113].Th17 cells have complex biological functions and evi-dence suggests that these cells may paradoxically alsocontribute to anti-tumor immunity. With infusion of invitro-generated Th17 cells, lungs of mice bearing B16melanoma tumors had elevated dendritic cell and acti-vated T cell recruitment, as well as elevated CCL20 andCCL2 expression, chemokines known to recruit theseanti-tumor immune cells [114]. Increased IL-21 levels,also produced by Th17 cells, can induce tumor regres-sion through expansion of CD8+ tumor-infiltrating lym-phocytes in NSCLC as well as ovarian cancer andmelanoma [115, 116] (Fig. 4). Moreover, high counts ofpleural Th17 cells are associated with increased survivalof NSCLC (lung AC and SqCC histologies) in humanMPEs [117]. These studies reveal differential functionsof Th17 cells, thus further investigation into their bio-logical roles and clinical relevance in cancer develop-ment is warranted.Quantitative relationships between Th17s and Tregs inlung cancer prognosisWhile various immune cell populations have been stud-ied extensively in the context of cancer biology, the fieldhas primarily focused on individual cell populations.More recently, cancer immunology has shifted towards amore integrated understanding of potential interactionsamong immune cell populations within the tumormicroenvironment, including a focus on cellular ratios,crosstalk and phenotype plasticity in the context of cancerprognosis. Advancements in this framework include thedevelopment of an immunoscore as a potential compo-nent of cancer classification with prognostic relevanceacross a number of different tumor types, includingNSCLC [118–121]. In addition to lung cancer, changes toTreg/Th17 levels have been observed in hematologicaland other solid tumor types in addition to autoimmunediseases and viral and bacterial infections, indicating thatthe balance of these two subsets plays an importantrole in regulating inflammation and cancer develop-ment [122–124]. Although both Treg and Th17 cellsexert a diverse set of cancer-related functions (Figs. 3and 4), these CD4+ T cell subsets may have opposingprognostic values in lung cancer, with a higher ratioof Tregs to Th17s correlating with more aggressiveand advanced-staged malignancies [125, 126]. Thebalance of Treg and Th17 cells has been assessed ininflammation resulting from autoimmune disease,viral infections and bacterial infections [127–134]. Inaddition, Th17 and Treg cells are broadly consideredto play pro- and anti-inflammatory roles, respectively,though it should be noted T cell plasticity allows fora functional continuum between these two CD4+ Tcell subsets [135, 136]. In summation, the balance ofthese two CD4+ T cell subsets at local tumor and sys-temic sites appears to be strongly associated withlung cancer development, progression and prognosis.The Treg/Th17 ratio and lung cancer prognosis has beenassessed in peripheral blood. Peripheral blood of NSCLCpatients is characterized by a significantly higher percent-age of Th17 (CD4+IL-17+) and Treg cells (CD4+CD25+FoxP3+) compared to individuals without cancer. How-ever, in NSCLC patients, the levels of these two CD4+ Tcell subsets were inversely correlated in peripheral blood[137] (Fig. 6). Serum Th17 cells are known to positivelycorrelate with IL-1β, IL-6, IL-23, while Tregs are known topositively correlate with TGF-β1 and IL-10 [137] (Fig. 6).NSCLC patients with Stage IV disease had higher Treg/Th17 ratios compared to patients with Stage I-III disease(Fig. 6). Conversely, the ratio was determined in anotherstudy to inversely correlate with serum levels of carcinoem-bryonic antigen (CEA), an oncofetal marker elevated inlung cancers with poor prognosis [137]. These studies high-light the variability of CD4+ T cell ratios in cancer progres-sion, which certainly warrants further exploration [126].In addition to assessing Treg/Th17 ratios in a systemiccontext in peripheral blood, proportions of these CD4+T cell subsets have been characterized in biological fluidsthat are local to the lung, including pleural fluid(Table 2). Malignant and non-malignant pleural effu-sions (NMPE) derived from chronic inflammatory lungdiseases, such as lung cancer and tuberculosis, havelower Treg and higher Th17 levels compared to non-chronic pleural effusions [138]. However, upon stimula-tion, CD4+ T cells in MPE secrete higher levels of IFN-γ,IL-6 and IL-17A and lower levels of IL-10 compared tothat of non-malignant tuberculous pleural effusions(TPE) over time, suggesting that Th17s may maintain apro-inflammatory environment in the pleural cavity oflung cancer patients [138] (Fig. 6). Conversely, an ele-vated Treg/Th17 ratio was found in MPEs when com-pared to NMPEs, such as parapneumonic pleuraleffusions (PPE) [139]. Furthermore, MPEs from lungcancer patients with a high Treg/Th17 ratio were foundto correlate with poor survival [139]. These differencesmay be partially accounted for by the complex roles ofinflammation in pro-tumor and anti-tumor activitiesduring the course of cancer development [140].Marshall et al. Molecular Cancer  (2016) 15:67 Page 10 of 15As evidenced by the studies mentioned above, theTreg/Th17 ratio has been primarily assessed in peripheralblood and pleural effusion samples. Collection of liquidbiopsies requires less invasive procedures and are advanta-geous for longitudinal studies, as sampling can be con-ducted at multiple time points [141]. Future longitudinalstudies will be very valuable to elucidating potential tem-poral relationships of these cell types during lung cancerpathogenesis and their clinical relevance. Treg and Th17cell levels have been assessed in lung tumor biopsies, al-though these cell types are typically assessed individuallyusing single markers on tissues sections, and Treg/Th17 ra-tios have not yet been reported for lung tumors. Part of thedifficulty in assessing Tregs and Th17 cells in solid tumorsis that both cell types are most accurately identified usingmultiple phenotypic markers and are therefore more amen-able to analyses by single cell analytical methods, such asflow cytometry [142]. The advancement of multispectralimaging analyses of tissue sections may allow for Treg/Th17 ratio assessment in lung tumour biopsies in the fu-ture, while also providing extended insights into the clinicalrelevance of the spatial relationships of immune cells withinthe tumor microenvironment [143, 144].While Th17s and Tregs have unique roles in thetumor microenvironment, interpretations of this ratiomay be confounded by the presence of IL-17+FoxP3+ Tcells, an intermediate Treg/Th17 phenotype that may berelevant to tumorigenesis [145] (Fig. 6). IL-17+FoxP3+ Tcells may be generated from cytokine-dependent repro-gramming of Tregs [146]. IL-17+FoxP3+ T cells havebeen implicated in autoimmune disease and solid cancerdevelopment, including inflammatory bowel disease andesophageal, colon and lung cancers [147–150]. In lungcancer, a CD45RA−CD45RO+FoxP3hi subset enriched inNSCLC is characterized by increased RORγt and IL-17expression [151]. Elucidation of specific molecular fea-tures and functions that IL-17+FoxP3+ T cells possessmay reveal how this intermediate cell type influences in-flammation in the tumor microenvironment, and mayimprove understanding of the Treg/Th17 ratio in cancerprognosis. The link between the balance of Tregs/Th17cells and lung cancer prognosis underscores the clinicalrelevance of these cell types as biomarkers and potentialtherapeutic targets. With the current development ofTh17 and Treg-targeted therapies, further studies asses-sing the complex roles of these immune cell types in lungcancer are needed if they are to be implemented in theclinic as a novel lung cancer treatment strategy [152–154].ConclusionsInflammation mediated by infiltrating immune cellsplays a key role in cancer pathogenesis. Among these, Tcells display critical and diverse roles in the establish-ment and suppression of inflammation within the tumormicroenvironment. These include Tregs and Th17s,CD4+ T cells which have been observed to mechanisticallypromote tumorigenesis, cancer progression and metastasisthrough immunosuppressive and pro-inflammatory func-tions. Specifically, Treg and Th17 cells in the tumormicroenvironment modulate cytokine and chemokineproduction, promote immune cell recruitment and helpregulate anti-tumor and pro-tumor immune cell activationstates. Altered levels of these immune cell populationsand their respective functions can facilitate lung cancerprogression and metastasis. Furthermore, the balance ofthese CD4+ T cell populations at local and systemic sitesmay be clinically relevant in evaluating lung cancer prog-nosis. Further investigations are warranted to fullycharacterize the mechanistic effects and prognostic valueof these immune cell populations in the context of cancer.AbbreviationsAC: Adenocarcinoma; BAL: Bronchoalveolar lavage; CCL: Chemokine (C-Cmotif) ligand; CEA: Carcinoembryonic antigen; COPD: Chronic obstructivepulmonary disease; COX2: Cyclooxygenase 2; CRP: C-reactive protein;CSF: Colony-stimulating factor; CTL: Cytotoxic T lymphocyte;CXCL: Chemokine (C-X-C motif) ligand; IFN-γ: Interferon gamma;IL: Interleukin; JAK/STAT: Janus kinase/signal transducer and activator oftranscription; MPE: Malignant pleural effusion; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NK: Natural killer; NNK: Nicotine-derived nitrosamine ketone; NSCLC: Non-small cell lung cancer;NTHi: Nontypeable Haemophilus influenzae; RORγt: Retinoic acid receptor-related orphan receptor gamma t; ROS: Reactive oxygen species; SCLC: Smallcell lung cancer; SqCC: Squamous cell carcinoma; TGF-β: Transforminggrowth factor beta; Th: T helperTable 2 Characterization of Treg/Th17 ratios in malignant pleural effusionsPleural effusion type compared Observed characteristics of malignant pleural effusion (Relative to pleural effusion type compared) ReferencesParapneumonic ↑ Treg (CD4+CD25+FoxP3+)/Th17(CD4+IL-17+) ratio↑ Foxp3/RORγt ratio[139]Malignant (with low Treg/Th17 ratio) ↓ Overall survival with high Treg/Th17 in malignant pleural effusionsNon-chronic diseases ↓Treg (CD4+CD25+CD127low/−)/Th17 (CD3+CD4+RORγt+) ratio a↑ IL-17A+CD4+ cells↓ CCR6+ Th17 cells[138]Tuberculous No significant difference in Treg (CD4+CD25+CD127low/−)/Th17 (CD3+CD4+RORγt+) ratio↑ IL-17A+CD4+ cells↓ CCR6+ Th17 cellsa For consistency, cell ratios are presented as Treg/Th17Marshall et al. Molecular Cancer  (2016) 15:67 Page 11 of 15AcknowledgementsNot applicable.FundingThis work was supported by grants from the Canadian Institutes for HealthResearch (CIHR, FDN-143345, MOP-123273, MOP-110949), the CanadianCancer Society (CCSRI #702535 and #702520), the National Sanitarium Associationand the Terry Fox Research Institute. E.A.M. is supported by a British ColumbiaCancer Studentship; S.H.Y.K., E.C.H., D.A.R, E.A.V. and K.S.S.E. by CIHR FrederickBanting and Charles Best Canada Graduate Scholarships and Four Year DoctoralFellowships from the University of British Columbia. D.D.B.S is supported by aVanier Canada Scholarship and a Killiam Doctoral Scholarship. K.L.B and W.W.L.are Michael Smith Foundation for Health Research Biomedical Research Scholars.Availability of data and materialsNot applicable.Authors’ contributionsEAM, KWN and SHYK performed literature search and drafted the manuscript.SHYK and JCE produced the figures and illustrations. All authors contributedto the design of the article, participated in the writing and analysis ofinformation, and approved the final version to be published. KLB, WWL, SL,NA and WLL are the principal investigators.Authors’ informationE.A.M., K.W.N and S.H.Y.K. contributed equally to the preparation of thisarticle. This manuscript was authored with critical input from leading expertsin various aspects of lung cancer biology. A.W.P, E.C.H., E.M.C., K.W.B., K.W.N.and N.A. provided expertise in immunology. J.C.E. provided expertise in lungcancer histopathology. D.A.R., D.D.B.S., E.A.V., K.S.S.E., S.L., V.D.M., W.L.L. andW.W.L. provided expertise in lung tumor molecular biology.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participateNot applicable.Author details1Department of Integrative Oncology, British Columbia Cancer Agency,Vancouver, Canada. 2Department of Pathology and Laboratory Medicine,University of British Columbia, Vancouver, Canada. 3Departments ofMicrobiology and Immunology, University of British Columbia, Vancouver,Canada. 4Department of Zoology, University of British Columbia, Vancouver,Canada. 5British Columbia Cancer Research Centre Centre, Vancouver,Canada.Received: 14 July 2016 Accepted: 18 October 2016References1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancerstatistics. CA Cancer J Clin. 2011;61(2):69–90.2. Cancer facts and figures. 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