Interleukin-17 and type 17 helper T cells in cancer management and research

Figures & data

Figure 1 Differentiation and functional flexibility of Th17 in TME.

Notes: DC “educate” naïve CD4⁺ T cells in the draining lymph nodes. DC produced TGF-β, IL-6, IL-23, and IL-1β, all necessary for Th17 development. Th17 cells accumulate in the TME through the production of cytokines such as CCL20 and CCL22. In the presence of IL-6 and low TGF-β, uncommitted Th0 cells differentiate into poorly pathogenic IL-10⁺ Th17. IL-23R is therefore upregulated, allowing IL-23 to stabilize the phenotype and induce the production of IFN-γ. In tumor tissues, effector memory T cells can be converted into Th17. APC such as DC and TAM are robust producers of IL-1β and IL-23, which are involved in the polarization of Th17 (IL-10⁺ non-pathogenic/protumoral versus IFN-γ⁺ pathogenic). Infiltrating Treg can differentiate into Th17 in the presence of IL-6, IL-1β, and IL-23.
Abbreviations: APC, antigen-presenting cells; CCL, chemokine (C-C motif) ligand; CD, cluster of differentiation; DC, dendritic cells; Foxp3, forkhead box P3; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-γ, interferon gamma; IL, interleukin; RORγt, retinoic acid receptor related orphan receptor gamma; STAT3, signal transducer and activator of transcription 3; TAF, tumor associated fibroblast; TAM, tumor associated macrophage; TBET, T-box transcription factor; Th17, T helper 17 cells; TGF-β, transforming growth factor beta; TME, tumor microenvironment; Treg, regulatory T cells; Tum, tumor; Th0, Th cells.

Table 1 List of experimental murine models analyzing the roles of IL-17/IL-23 in tumor immunity

Cancer type	Tumor tissue	Immune mediator	Functional analysis	Outcome	Statistics	Ref
Melanoma	B16	Th17	Th17. Th1 for tumor eradication; IFN-γ-dependent	Positive	One-way ANOVA with Bonferroni correction (vitiligo)	^Citation47
Melanoma	B16	Th17	Treg converted to Th17 by IL-6 from pDC Increased CD8+ T cells and antitumor effect	Positive	Tukey honestly significant difference test	^Citation41
Melanoma	B16	Tc17	Adoptive transfer of Tc17; enhanced antitumor immunity	Positive	None	^Citation93
Melanoma	B16-F10	Th17	Adoptive transfer Th17 cells; CCL20-dependent DC and CTL recruitment; decreased tumor growth	Positive	Student’s t-test, n=4–5 mice	^Citation53
Melanoma	B16	IL-23	IL-23 as vaccine adjuvant; tumor-specific CD8+ T cell responses	Positive	ANOVA-repeated measures test and Wilcoxon’s rank-sum test; Nonparametric Kruskal–Wallis test; n=5	^Citation88
Colon	MC38	Th17/IL-17	Increased tumor growth in IL-17-deficient mice	Positive	Mann–Whitney U and χ^2 tests; n=5	^Citation55
Ovarian	ID8	Th17	Increased tumor growth; myeloid cell recruitment	Negative	Two-tailed Student’s t-test with Welch’s correction or Mann–Whitney test; n=60	^Citation64
Fibrosarcoma	CMS-G4	IL-17/γδ-T	IL-17-producing γδ+ T cells promoted angiogenesis	Negative	Two-tailed Student’s t-test (tumor volume); n=5	^Citation66
Skin	DMBA/TPA	IL-17	Decreased tumor in IL-17 KO mice; STAT3-dependent	Negative	Unpaired t-test (WT, n=19; IL-17−/−, n=11)	^Citation54
Melanoma	B16 and MB49	Th17	Th17 promotes tumor growth; IL-6/STAT3-dependent	Negative	Unpaired t-test. Two-way ANOVA test (tumor growth)	^Citation60
Cervical cancer	HeLa, IC1	IL-17	IL-17 increases tumor cell growth in nude mice	Negative	Mann–Whitney test (tumor size); n=8–10	^Citation58
NSCLC	Variety cell lines	IL-17	CXCR2-dependent angiogenesis in SCID mice	Negative	Unpaired two-tailed Student’s t-test (tumor volume) n=7	^Citation61
Multiple	Variety cell lines	IL-17	IL-17 promotes tumor growth; MDSC recruitment	Negative	Two-tailed Student t-test; n=5	^Citation62
Multiple	Variety of cell lines	IL-17	Resistance to anti-VEGF therapy via G-CSF-mediated MDSC recruitment	Negative	Two-tailed Student’s t-test; n=5–8	^Citation63
Fibrosarcoma, colon	MCA205, MC38	IL-17	IL-17 promotes angiogenesis via stimulation of vascular endothelial cell migration and induction of pro-angiogenic factors	Negative	Unpaired two-tailed Student’s t-test; n=6–7	^Citation57
Melanoma Breast cancer	B16-F10 4T1	IL-17	PPARγ-induced SOCS3 prevents IL-17-mediated cancer growth	Negative	Mann–Whitney U test and comparison of categorical data by Fisher’s exact test	^Citation67
Multiple	Variety of cell lines	IL-23	IL-23 promotes tumor incidence and growth	Negative	Student’s t-test; Kruskal–Wallis test/Dunn’s multiple comparison test/Tukey’s multiple comparison test/Wilcoxon matched pairs test; n=3–7	^Citation87

Abbreviations: ANOVA, analysis of variance; CCL, chemokine (C-C motif) ligand; CTL, cytotoxic T lymphocytes; CXCR, chemokine (C-X-C motif) receptor; CD8, cluster of differentiation 8; DC, dendritic cells; DMBA, 7,12-dimethylbenz-alpha-anthracene; G-CSF, granulocyte colony-stimulating factor; IFN-γ, interferon gamma; IL, interleukin; KO, knockout; MDSC, myeloid-derived suppressor cells; NSCLC, non-small-cell lung carcinoma; pDC, plasmacytoid dendritic cells; PPARγ, peroxisome proliferator-activated receptor gamma; SCID, severe combined immunodeficiency; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; Tc17, Th17 or IL-17-producing CD8⁺ T cells; Th, T helper; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; Treg, regulatory T cells; VEGF, vascular endothelial growth factor.

Figure 2 Role of IL-17 in tumor progression.

Notes: IL-17 in the TME initiates the recruitment of immune effectors through the induction of chemokines, cytokines, and growth factors secretion by tumor cells, tumor-infiltrating fibroblasts (TAF), and endothelial cells. IL-17 induces the production by tumor cells of CXCL9 and CXCL10, which recruit NK cells and CTL or CCL20, which recruits DC, to mediate antitumor immune response. IL-17 also triggers the production of CXCL1, CXCL5, and CXCL8 by other types of tumors and TAF to mediate pro-angiogenic activities. VEGF and PGE2, produced by tumor cells and TAF, also contribute to angiogenesis and tumor growth. G-CSF produced by tumor cells and TAF will impact the recruitment of myeloid progenitors and disturb local granulopoiesis, resulting in the accumulation of MDSC. Finally, IL-17/IL-17R interactions lead to the production of IL-6, an important tumor growth and survival factor, via the activation of the oncogenic STAT3.
Abbreviations: CCL, chemokine (C-C motif) ligand; CTL, cytotoxic T lymphocytes; CXCL, chemokine (C-X-C motif) ligand; DC, dendritic cells; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; MDSC, myeloid-derived suppressor cells; NK, natural killer; PGE2, prostaglandin E2; STAT3, signal transducer and activator of transcription 3; TAF, tumor associated fibroblasts; TAM, tumor associated macrophages; Th1, T helper 1; TME, tumor microenvironment; TNF, tumor necrosis factor; Treg, regulatory T cells; VEGF, vascular endothelial growth factor.

Table 2 List of studies in humans analyzing the links between cancer type and IL-17/Th17 detection

Cancer types	Biological samples	IL-17	Functional analysis	Outcome	Statistics	Ref
Ovarian	Fresh tumor/FACS	Th17	Increased IFN-γ^+ T cells	N/A	Positive correlation Th17 versus Th1 or CTL	^Citation50
	Ascitis/ELISA	IL-17	CXCL9, CXCL10 production by cancer cells	Positive	Kaplan–Meier (OS/IL-17); n=85	^Citation50
	FFPE/IHC	IL-17	Response to chemotherapy	Positive	Multivariate Cox proportional; n=94	^Citation106
Colorectal	Frozen tissue/RT-PCR	IL-17 mRNA	Th17-related cluster of genes (Il17a, Rorc, CCL24)	Negative	Kaplan–Meier (DFS/Th17 cluster); n=125	^Citation13
	FFPE/IHC	None
	FFPE/IHC, IF	IL-17^+ MAC	Increased VEGF and MVD^a	Negative	Kaplan–Meier, log-rank test (OS/IL-17^+); n=52	^Citation75
Breast	FFPE/IHC	IL-17	N/A	Negative	Kaplan–Meier, log-rank test (DFS/IL-17^+); n=207 Uni–Multivariate Cox proportional	^Citation107
	Frozen tissue/RT-PCR	IL-17 mRNA	IL-17/Foxp3 correlation; CXCL8, VEGF (angiogenesis)	Negative	Spearman test; n=39	^Citation108
Lung	MPE,* blood/FACS	Th17	CCR4^+CCR6^+ Th17; CCL20^+ cells	Positive	Kaplan–Meier, log-rank test (OS/%IL-17); n=15 Uni–Multivariate Cox proportional	^Citation74
	FFPE/IHC	IL-17	Lymphatic vessel density	Negative	Kaplan–Meier, log-rank test (OS, DFS/IL-17^+); n=52 Uni–Multivariate Cox proportional	^Citation109
	Serum/ELISA	IL-17	Higher IL-17 in serum of NSCLC	Negative	Correlation TNM/serum IL-17; n=60	^Citation110
	Tissue/RT-PCR	IL17A mRNA	Promote metastasis in mice	Negative	Correlation invasion/mRNA Il17a; n=18
ESCC*	FFPE/IHC	IL-17	Recruitment of CD1a^+ DC	Positive	Kaplan–Meier, log-rank test (OS/CD1a^+ cells); n=181	^Citation65
	FFPE/IHC	IL-17	Recruitment of NK and CD8^+ T cells	Positive	Kaplan–Meier, log-rank test (OS/IL-17^+ cells); n=181 Uni–Multivariate Cox proportional	^Citation73
	FFPE/IHC, IF	IL-17^+ mast cells	Recruitment of CD8^+ T cells and macrophages in muscularis propria	Positive	Kaplan–Meier, log-rank test (OS/IL-17^+); n=215 Multivariate Cox proportional	^Citation30
Gastric	Blood, fresh tumor/FACS	IL-17	Tumor recruitment (versus blood)	N/A	Paired t-test (blood versus tumor)	^Citation71
	Serum/ELISA	IL-17	None	Positive	Paired t-test (blood versus tumor) Kaplan–Meier (OS/serum IL-17); n=85 Multivariate Cox proportional	Kaplan–Meier (OS/serum IL-17); n=85 Multivariate Cox proportional
	FFPE/IHC	IL-17	No correlation IL-17^+ and CD8^+ cells	Positive	Kaplan–Meier (OS/IL-17^+ cells); n=192 Multivariate Cox proportional	^Citation72
NPC*	FFPE/IHC	IL-17	GZB, Foxp3 expression	None	Kaplan–Meier, log-rank test (OS, PFS/IL-17^+); n=106 Uni–Multivariate Cox proportional	^Citation111
HCC*	Fresh tumor/FACS	Th17	Memory CCR4^+CCR6^+ Th17 in tumor	N/A	Linear regression (MVD/%Th17); n=28	^Citation81
	Frozen tissue/RT-PCR	IL-17	CCL20 mRNA in tumor	N/A	N/A
	FFPE/IHC; frozen/IF		CD4^+/IL-17^+ ; CD4^−/IL-17^+ cells	Negative	Kaplan–Meier, log-rank test (OS, DFS/IL-17^+); n=108 Multivariate Cox proportional
	FFPE/IHC	IL-17/IL-17RE	None	Negative	Kaplan–Meier (OS, TTR/IL-17^+ cells); n=300 Multivariate Cox proportional	^Citation112

Abbreviations: CCL, chemokine (C-C motif) ligand; CCR, chemokine receptor; CD, cluster of differentiation; CTL, cytotoxic T lymphocytes; CXCL, chemokine (C-X-C motif) ligand; DC, dendritic cells; DFS, disease-free survival; ELISA, enzyme-linked immunosorbent assay; ESCC, esophageal squamous cell carcinoma; FACS, fluorescence-activated cell sorting; FFPE, formalin-fixed paraffin embedded; Foxp3, forkhead box P3; GZB, granzyme B; HCC, hepatocellular carcinoma; IF, immunofluorescence; IFN-γ, interferon gamma; IHC, immunohistochemistry; IL, interleukin; IL-17RE, IL-17R subunit E; MAC, macrophage; MPE, malignant pleural effusion; mRNA, messenger RNA; MVD, microvessel density; N/A, not applicable; NK, natural killer; NPC, nasopharyngeal carcinoma; NSCLC, non-small-cell lung carcinoma; OS, overall survival; PFS, progression-free survival; RT-PCR, reverse transcription polymerase chain reaction; Th, T helper; TNM, tumor-node-metastase classification; TTR, time to recurrence; VEGF, vascular endothelial growth factor.

Table 3 Drugs affecting IL-17 and Th17 functions in preclinal and clinical development

Drugs	Properties	Company	Applications
Secukinumab	Anti-IL-17A Humanized mAb	AIN457 (Novartis)	Psoriasis, RA, MS, ankylosing spondylitis (Phase III)
Ixekizumab	Anti-IL-17A Humanized mAb	Ly2439821 (Eli Lilly)	Psoriasis, RA, ankylosing spondylitis (Phase II)
Brodalumab	Anti-IL-17R Human mAb	AMG-827 (Amgen)	Psoriasis, RA, asthma (Phase II)
Briakinumab	Anti-IL-12/p40 Human mAb	ABT-874 (Abbott)	Withdrawn
Ustekinumab	Anti-IL-12/p40 Human mAb	Stelara^® (Janssen Biotech Inc)	Psoriasis, psoriasis arthritis
MP-196	IL-23/p19	Effimune	N/A
Tocilizumab	Anti-IL-6R Humanized mAb	Actemra^® (Genentech)	RA
Anakinra	IL-1R antagonist	Kineret^® (Amgen)	RA, NOMID
OPB-31121	STAT3 inhibitor	OPB-31121 (Otsuka Pharmaceutical)	Advanced cancer (Phase I)
OPB-51602	STAT3 inhibitor	OPB-51602 (Otsuka Pharmaceutical)	Advanced cancer (Phase I)
AZD9150	STAT3 inhibitor	AZD9150 (ISIS Pharmaceutical)	Advanced cancer, lymphoma, HCC (Phase I/II)
SR1001	ROR inhibitor	Preclinical development	N/A
Vidofludimus	DHODH inhibitor	4SC-101 (4SCAG)	Crohn’s disease, UC (Phase II)
Tofacitinib	JAK inhibitor	Xeljanz^® (Pfizer)	RA
Vorinostat	HDAC inhibitor	Zolinza^® (Merck)	CTCL
Romidepsin	HDAC inhibitor	Istodax^® (Celgene)	CTCL

Notes: Secukinumab: Novartis International AG, Switzerland; Ixekizumab: Eli Lilly and Company, Indianapolis, IN, USA; Brodalumab: Amgen, Thousand Oaks, CA, USA; Briakinumab: Abbott Park, North Chicago, IL, USA; Ustekinumab: Janssen Biotech, Inc., CA, USA; MP-196: Effimune, Nantes, France; Tocilizumab: Actemra^® (Genentech), CA, USA; Anakinra: Amgen; OPB-31121: Otsuka Pharmaceutical, Tokyo, Japan; OPB-51602: Otsuka Pharmaceutical; AZD9150: Isis Pharmaceuticals Inc., San Diego, CA, USA; Vidofludimus: 4SC, Munich, Germany; Tofacitinib: Xelianz^® (Pfizer), New York, NY, USA; Vorinostat: Zolinza^® (Merck), Rahway, NJ, USA; Romidepsin: Istodax^® (Celgene), Summit, NJ, USA.

Abbreviations: CTCL, cutaneous T cell lymphoma; DHODH, dihydroorotate dehydrogenase; HCC, hepatocellular carcinoma; HDAC, histone deacetylase; IL, interleukin; JAK, Janus kinase; mAb, monoclonal antibody; MS, multiple sclerosis; N/A, not applicable; NOMID, neonatal onset multisystem inflammatory disease; RA, rheumatoid arthritis; ROR, retinoic acid receptor related orphan receptor; STAT3, signal transducer and activator of transcription 3; UC, ulcerative colitis.

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