IL-17-Producing Cells in Tumor Immunity: Friends or Foes?

Da-Sol Kuen; Byung-Seok Kim; Yeonseok Chung

doi:10.4110/in.2020.20.e6

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Kuen, Kim, and Chung: IL-17-Producing Cells in Tumor Immunity: Friends or Foes?

Review Article

Immune Netw 2020;20(1):e6.

Published online: 4 February 2020

DOI: https://doi.org/10.4110/in.2020.20.e6

IL-17-Producing Cells in Tumor Immunity: Friends or Foes?

Da-Sol Kuen^1,², Byung-Seok Kim¹, Yeonseok Chung^1,^2,^*

¹Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea

²BK21 Plus Program, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea

^*Correspondence to Yeonseok Chung Laboratory of Immune Regulation and BK21 Plus Program, Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea. E-mail: yeonseok@snu.ac.kr

Conflict of Interest The authors declare no potential conflicts of interest.

Received 29 December 2019 Revised 25 January 2020 Accepted 26 January 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

IL-17 is produced by RAR-related orphan receptor gamma t (RORγ t)-expressing cells including Th17 cells, subsets of γδ T cells and innate lymphoid cells (ILCs). The biological significance of IL-17-producing cells is well-studied in contexts of inflammation, autoimmunity and host defense against infection. While most of available studies in tumor immunity mainly focused on the role of T-bet-expressing cells, including cytotoxic CD8⁺ T cells and NK cells, and their exhaustion status, the role of IL-17-producing cells remains poorly understood. While IL-17-producing T-cells were shown to be anti-tumorigenic in adoptive T-cell therapy settings, mice deficient in type 17 genes suggest a protumorigenic potential of IL-17-producing cells. This review discusses the features of IL-17-producing cells, of both lymphocytic and myeloid origins, as well as their suggested pro- and/or anti-tumorigenic functions in an organ-dependent context. Potential therapeutic approaches targeting these cells in the tumor microenvironment will also be discussed.

Keywords: Tumor microenvironment, Th17 cells, Interleukin-17, T-lymphocytes

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Figure 1.

Type17 compartments in the tumor microenvironment. The tissue-specific niche, and the stage of cancer progression dictate the heterogeneous composition of type 17 compartment in the tumor microenvironment. Both innate and adaptive arms of the immune system are capable of producing IL-17. Studies involving both CD4⁺ Th17 and CD8⁺ Tc17 T-cells reported protumorigenic or anti-tumorigenic roles. Anti-tumorigenic Th/c17 cells co-secrete IFN-γ, and exhibit type 1–17 hybrid phenotypes that lead to enhanced dendritic cell infiltration and tumor-Ag presentation, type 1-helper function or Tc1 conversion in the case of Tc17 cells under the appropriate cytokine stimuli. However, an increasing amount of evidence illustrate the protumorigenic mechanisms (highlighted in blue) of type 17 cells within the immunosuppressive endogenous microenvironment within the growing tumor. Largely, they work by two broad mechanisms: 1) the IL-17 mediated recruitment of immunosuppressive myeloid compartment, either directly by type 17 cells or indirectly by cancer cells in a chemokine dependent manner, 2) cancer intrinsic IL-17 signaling, leading to enhanced cancer cell survival, EMT and angiogenesis promotion. EMT, epithelial–mesenchymal transition; TAM, tumor-associated macrophage.

Figure 2.

Developing strategies to utilize type 17 axis for anti-cancer therapy. Currently developing strategies to transform the type 17 landscape within the tumor microenvironment for successful cancer elimination are illustrated. TAM, tumor-associated macrophage.

Table 1.

Summary of findings from mouse cancer model studies: function of type 17 lymphocytes

Cancer model	Sub-type	Function of type 17 cells (pro- or anti-tumorigenic?)	Ref.
Subcutaneous injection	EL4, CT26	Pro-tumorigenic	(11)
	B16 melanoma	Anti-tumorigenic	(12)
	MC38	Anti-tumorigenic	(13)
	KPC, Braf-Pten, B16-melanoma	Pro-tumorigenic	(14)
	Hepa1–6 HCC	Pro-tumorigenic	(15)
	MA782 (orthotopic)	Pro-tumorigenic	(16)
	4T1 (orthotopic)	Pro-tumorigenic	(16,17)
Intraperitoneal injection	ID8 ovarian cancer	Pro-tumorigenic	(18,19)
Intravenous injection	B16 melanoma, LLC	Anti-tumorigenic	(20)
	MC38	Anti-tumorigenic	(13)
Oncogene-activated	Constitutive MYC expression in early B-cells	Pro-tumorigenic	(21)
	K14 ^Cre xCdh1 ^f/f xTrp53 ^f/f	Pro-tumorigenic	(22)
	(KEP) mice spontaneous breast cancer
	Kras ^G12D xCCSP ^Cre Lung Cancer	Pro-tumorigenic	(23)
	Kras ^LSL-G12D xp53 ^f/f xSftpc ^Cre Lung Cancer	Pro-tumorigenic	(24)
	Pten ^f/f xSMAD4 ^f/f xCCSP ^Cre Lung Cancer	Anti-tumorigenic	(25)
Carcinogen-induced	DMBA/TPA-induced skin cancer/squamous cell carcinoma	Pro-tumorigenic	(26,27)
	AOM DSS APCmin ETBF-induced colon cancer	Pro-tumorigenic	(28–30)
Inflammation-accelerated	Helicobacter hepaticus-infected/AOM-treated129SvEvS6. Rag2^−/−	Pro-tumorigenic	(31)

AOM, azoxymethane; DMBA, 7,12-dimethylbenz[a]anthracene; DSS, dextran-sulfate sodium; ETBF, Enterotoxigenic Bacteroides fragilis; HCC, hepatocellular carcinoma; LLC, Lewis lung carcinoma; TPA, 12-O-tetradecanoylphorbol-13-acetate.

Table 2.

Summary of type 17 T-cell types by human cancers and its associated prognosis

Cancer Type	Endogenous, tumor-infiltrating type 17 T-cells found	Overall survival	Ref.
Acute leukemia	Th17	Improved	(32)
Acute myeloid leukemia	Tc17	Poor	(33)
Breast	Th17	Poor^*	(34,35)
Colorectal cancer	gdT17, Th17	Poor	(28–38)
Cervical carcinoma	Th17	Improved^†	(39)
Cervical squamous cell carcinoma	CD3⁺ IL17⁺	Improved^‡	(40)
Esophageal squamous cell	IL17⁺ cells	Improved	(41,42)
carcinoma
Gastric carcinoma	Th17	Poor	(43,44)
Hepatocellular carcinoma	Tc17, Th17	Poor	(45–47)
Lung cancer	Th17	Improved	(48)
Lung carcinoma	Th17, gdT17	Improved	(49,50)
Melanoma	Th17, Tc17	Poor	(51)
Myeloma	Th17	Poor	(52,53)
Nasopharyngeal	Th17, Tc17	Improved?	(54)
Nasopharyngeal carcinoma	IL17⁺ cells	No correlation	(54,55)
Non-small cell lung	Th17	Poor	(56,57)
Ovarian	Th17	Improved	(58,59)
Pancreatic	Th17	Poor	(60)
Prostate	Th17, NKT17	Improved^§	(61,62)
Renal cell carcinoma	Th17	Improved	(63)
Small cell lung	Th17 (peripheral)	Improved	(64)

^* Improved survival was observed in non-inflamed triple negative breast cancer.

^† In cervical carcinoma, IL-17 level as a whole was associated with poor outcome, due to the pro-tumorigenic contributions of IL-17 producing neutrophils.

^‡ Prognosis for IL-17+ cells in general was poor for cervical squamous cell carcinoma.

^§ The prognosis for IL-17 producing cells in hormone-resistant prostate cancer.

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