Journal List > Immune Netw > v.20(1) > 1148278

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

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.

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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.
in-20-e6f1.tif
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.
in-20-e6f2.tif
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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