Indoleamine-2,3-Dioxygenase in Thyroid Cancer Cells Suppresses Natural Killer Cell Function by Inhibiting NKG2D and NKp46 Expression via STAT Signaling Pathways

Natural killer (NK) cells are key players in the immune system. They use receptors on their cell surface to identify target cells. However, to escape being killed by the immune system, cancer cells such as thyroid cancer cells, use various methods to suppress the function of NK cells. Thus, this study aims to elucidate how thyroid cancer cells downregulate NK cell function in a co-culture system. We found that thyroid cancer cells suppress NK cell cytotoxicity and inhibit the expression of activating receptors, such as NKG2D and NKp46, by regulating indoleamine 2,3-dioxygenase (IDO). Also, thyroid cancer cells produce kynurenine using IDO, which causes NK cell dysfunction. Kynurenine enters NK cells via the aryl hydrocarbon receptor (AhR) on the surfaces of the NK cells, which decreases NK cell function and NK receptor expression via the signal transducer and activator of transcription (STAT) 1 and STAT3 pathways. In addition, STAT1 and STAT3 directly regulated the expression of NKG2D and NKp46 receptors by binding to the promoter region. Conclusively, NK cell function may be impaired in thyroid cancer patients by IDO-induced kynurenine production. This implies that IDO can be used as a target for thyroid cancer therapeutics aiming at improving NK cell function.

[1]  É. Vivier,et al.  Natural killer cells and other innate lymphoid cells in cancer , 2018, Nature Reviews Immunology.

[2]  Haiyoung Jung,et al.  Prostaglandin E2 Secreted by Thyroid Cancer Cells Contributes to Immune Escape Through the Suppression of Natural Killer (NK) Cell Cytotoxicity and NK Cell Differentiation , 2018, Front. Immunol..

[3]  P. Xue,et al.  The Aryl Hydrocarbon Receptor and Tumor Immunity , 2018, Front. Immunol..

[4]  K. Satyshur,et al.  Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR) , 2017, The Journal of Biological Chemistry.

[5]  V. Sexl,et al.  STATs in NK-Cells: The Good, the Bad, and the Ugly , 2017, Front. Immunol..

[6]  C. Tremblay,et al.  Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection , 2016, Journal of Virology.

[7]  N. Cacalano Regulation of Natural Killer Cell Function by STAT3 , 2016, Front. Immunol..

[8]  J. Routy,et al.  The Kynurenine Pathway Is a Double-Edged Sword in Immune-Privileged Sites and in Cancer: Implications for Immunotherapy , 2016, International journal of tryptophan research : IJTR.

[9]  Zhiyu Li,et al.  Research progress of indoleamine 2,3-dioxygenase inhibitors. , 2015, Future medicinal chemistry.

[10]  W. Wick,et al.  Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors , 2015, Front. Immunol..

[11]  V. Poli,et al.  Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance. , 2014, Blood.

[12]  É. Vivier,et al.  Natural cytotoxicity receptors and their ligands , 2014, Immunology and cell biology.

[13]  A. von Deimling,et al.  Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR , 2014, Oncotarget.

[14]  M. Veldhoen,et al.  The aryl hydrocarbon receptor in innate T cell immunity , 2013, Seminars in Immunopathology.

[15]  H. Rosen,et al.  Natural killer cells: multifaceted players with key roles in hepatitis C immunity , 2013, Immunological reviews.

[16]  K. Kataoka,et al.  The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells , 2013, Nature Communications.

[17]  D. Munn,et al.  Indoleamine 2,3 dioxygenase and metabolic control of immune responses. , 2013, Trends in immunology.

[18]  C. Biron,et al.  Changing partners at the dance , 2013, JAK-STAT.

[19]  P. Queirolo,et al.  Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. , 2012, Cancer research.

[20]  A. Kimura,et al.  Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages. , 2011, International immunology.

[21]  X. Pivot,et al.  Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. , 2011, Cancer research.

[22]  Dean Anthony Lee,et al.  Expansion, purification, and functional assessment of human peripheral blood NK cells. , 2011, Journal of visualized experiments : JoVE.

[23]  H. Weiner,et al.  The Aryl hydrocarbon Receptor (AhR) interacts with c-Maf to promote the differentiation of IL-27-induced regulatory type 1 (TR1) cells , 2010, Nature Immunology.

[24]  P. Queirolo,et al.  Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity , 2009, Proceedings of the National Academy of Sciences.

[25]  B. Stockinger,et al.  The aryl hydrocarbon receptor in immunity. , 2009, Trends in immunology.

[26]  O. Mazda,et al.  Interleukin-27 activates natural killer cells and suppresses NK-resistant head and neck squamous cell carcinoma through inducing antibody-dependent cellular cytotoxicity. , 2009, Cancer research.

[27]  M. Veldhoen,et al.  Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells , 2009, The Journal of experimental medicine.

[28]  Y. Fujii‐Kuriyama,et al.  Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells , 2008, Proceedings of the National Academy of Sciences.

[29]  J. Becker,et al.  Macrophage Migration Inhibitory Factor Contributes to the Immune Escape of Ovarian Cancer by Down-Regulating NKG2D1 , 2008, The Journal of Immunology.

[30]  Eric Vivier,et al.  Functions of natural killer cells , 2008, Nature Immunology.

[31]  A. Diefenbach,et al.  Dendritic cells prime natural killer cells by trans-presenting interleukin 15. , 2007, Immunity.

[32]  G. Rabinovich,et al.  Immunosuppressive strategies that are mediated by tumor cells. , 2007, Annual review of immunology.

[33]  Sun-Hee Kim,et al.  Novel Compound 2-Methyl-2H-pyrazole-3-carboxylic Acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) Prevents 2,3,7,8-TCDD-Induced Toxicity by Antagonizing the Aryl Hydrocarbon Receptor , 2006, Molecular Pharmacology.

[34]  L. Lanier,et al.  IL-21 Enhances Tumor Rejection through a NKG2D-Dependent Mechanism1 , 2005, The Journal of Immunology.

[35]  J. D. Di Santo,et al.  Roles for Common Cytokine Receptor γ-Chain-Dependent Cytokines in the Generation, Differentiation, and Maturation of NK Cell Precursors and Peripheral NK Cells in Vivo1 , 2005, The Journal of Immunology.

[36]  S. Kitano,et al.  Inhibition of indoleamine 2,3-dioxygenase suppresses NK cell activity and accelerates tumor growth. , 2003, Journal of experimental therapeutics & oncology.

[37]  R. Biassoni,et al.  Transforming growth factor β1 inhibits expression of NKp30 and NKG2D receptors: Consequences for the NK-mediated killing of dendritic cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Kazuyoshi Takeda,et al.  New aspects of natural-killer-cell surveillance and therapy of cancer , 2002, Nature Reviews Cancer.

[39]  G. Damonte,et al.  Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase , 2002, The Journal of experimental medicine.

[40]  Gerhard Opelz,et al.  Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells , 2002, The Journal of experimental medicine.

[41]  P. Bucher,et al.  DNA Binding Specificity of Different STAT Proteins , 2001, The Journal of Biological Chemistry.

[42]  C. O'Callaghan Molecular basis of human natural killer cell recognition of HLA-E (human leucocyte antigen-E) and its relevance to clearance of pathogen-infected and tumour cells. , 2000, Clinical science.

[43]  J. Ritz,et al.  Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4. , 2000, Blood.

[44]  U. Hadding,et al.  Interferon-γ-Induced Activation of Indoleamine 2,3-Dioxygenase in Cord Blood Monocyte-Derived Macrophages Inhibits the Growth of Group B Streptococci , 1998 .

[45]  J. Darnell STATs and gene regulation. , 1997, Science.

[46]  T. Hoey,et al.  Cooperative DNA Binding and Sequence-Selective Recognition Conferred by the STAT Amino-Terminal Domain , 1996, Science.

[47]  Milton W. Taylor,et al.  Relationship between interferon‐γ, indoleamine 2,3‐dioxygenase, and tryptophan catabolism , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  M. Edelstein,et al.  Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[49]  K. Kataoka,et al.  The ARNT-STAT3 axis regulates the differentiation of intestinal intraepithelial TCR alpha beta(+) CD8 alpha alpha(+) cells , 2013 .

[50]  E. Jaffee,et al.  Mechanisms of immune evasion by tumors. , 2006, Advances in immunology.

[51]  W. Leonard,et al.  The Jak-STAT pathway. , 2000, Molecular immunology.

[52]  U. Hadding,et al.  Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci. , 1998, The Journal of infectious diseases.

[53]  L. Lanier NK cell receptors. , 1998, Annual review of immunology.

[54]  J. Darnell,et al.  Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. , 1995, Annual review of biochemistry.