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IDO, PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The tumor microenvironment is profoundly immunosuppressive. This creates a major barrier for attempts to combine immunotherapy with conventional chemotherapy or radiation, because the tumor antigens released by these cytotoxic agents are not cross-presented in an immunogenic fashion. In this Focused Research Review, we focus on mouse preclinical studies exploring the role of immunosuppressive Tregs expressing the PTEN lipid phosphatase, and the links between PTEN+ Tregs and the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO has received attention because it can be expressed by a variety of human tumor types in vivo, but IDO can also be induced in host immune cells of both humans and mice in response to inflammation, infection or dying (apoptotic) cells. Mechanistically, IDO and PTEN+ Tregs are closely connected, with IDO causing activation of the PTEN pathway in Tregs. Genetic ablation or pharmacologic inhibition of PTEN in mouse Tregs destabilizes their suppressive phenotype, and this prevents transplantable and autochthonous tumors from creating their normal immunosuppressive microenvironment. Genetic ablation of either IDO or PTEN+ Tregs in mice results in a fundamental defect in the ability to maintain tolerance to antigens associated with apoptotic cells, including dying tumor cells. Consistent with this, pharmacologic inhibitors of either pathway show synergy when combined with cytotoxic agents such as chemotherapy or radiation. Thus, we propose that IDO and PTEN+ Tregs represent closely linked checkpoints that can influence the choice between immune activation versus tolerance to dying tumor cells.

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Fig. 1

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Abbreviations

CCR4:

C-C chemokine receptor type 4

FoxO3:

Forkhead box O3

GCN2:

General control nonderepressible-2

KO:

Knockout

mTOR:

Mechanistic target of rapamycin

mTORC:

mTOR kinase complex

PTEN:

Phosphatase and tensin homolog

Tregs:

Regulatory T cells

References

  1. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463–1469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kvistborg P, Philips D, Kelderman S, Hageman L, Ottensmeier C, Joseph-Pietras D, Welters MJ, van der Burg S, Kapiteijn E, Michielin O, Romano E, Linnemann C, Speiser D, Blank C, Haanen JB, Schumacher TN (2014) Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci Transl Med 6:254ra128

    Article  PubMed  Google Scholar 

  3. Cha E, Klinger M, Hou Y, Cummings C, Ribas A, Faham M, Fong L (2014) Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci Transl Med 6:238ra70

    Article  PubMed  PubMed Central  Google Scholar 

  4. Reissfelder C, Stamova S, Gossmann C, Braun M, Bonertz A, Walliczek U, Grimm M, Rahbari NN, Koch M, Saadati M, Benner A, Buchler MW, Jager D, Halama N, Khazaie K, Weitz J, Beckhove P (2015) Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis. J Clin Invest 125:739–751

    Article  PubMed  Google Scholar 

  5. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Daud AI, Loo K, Pauli ML, Sanchez-Rodriguez R, Sandoval PM, Taravati K, Tsai K, Nosrati A, Nardo L, Alvarado MD, Algazi AP, Pampaloni MH, Lobach IV, Hwang J, Pierce RH, Gratz IK, Krummel MF, Rosenblum MD (2016) Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J Clin Invest 126:3447–3452

    Article  PubMed  PubMed Central  Google Scholar 

  8. Verdegaal EM, de Miranda NF, Visser M, Harryvan T, van Buuren MM, Andersen RS, Hadrup SR, van der Minne CE, Schotte R, Spits H, Haanen JB, Kapiteijn EH, Schumacher TN, van der Burg SH (2016) Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature 536:91–95

    Article  CAS  PubMed  Google Scholar 

  9. Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10

    Article  PubMed  Google Scholar 

  10. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G (2015) Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28:690–714

    Article  CAS  PubMed  Google Scholar 

  11. Belvin M, Mellman I (2015) Is all cancer therapy immunotherapy? Sci Transl Med 7(315):315fs48

    Article  PubMed  Google Scholar 

  12. Medler TR, Cotechini T, Coussens LM (2015) Immune response to cancer therapy: mounting an effective antitumor response and mechanisms of resistance. Trends Cancer 1:66–75

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bezu L, Gomes-de-Silva LC, Dewitte H, Breckpot K, Fucikova J, Spisek R, Galluzzi L, Kepp O, Kroemer G (2015) Combinatorial strategies for the induction of immunogenic cell death. Front Immunol 6:187

    PubMed  PubMed Central  Google Scholar 

  14. Nishikawa H, Sakaguchi S (2014) Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 27:1–7

    Article  CAS  PubMed  Google Scholar 

  15. Bauer CA, Kim EY, Marangoni F, Carrizosa E, Claudio NM, Mempel TR (2014) Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J Clin Invest 124:2425–2440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Joshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP, Li A, DuPage M, Tammela T, Kerper NR, Farago AF, Robbins R, Crowley DM, Bronson RT, Jacks T (2015) Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity 43:579–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Thornton AM, Piccirillo CA, Shevach EM (2004) Activation requirements for the induction of CD4+ CD25+ T cell suppressor function. Eur J Immunol 34:366–376

    Article  CAS  PubMed  Google Scholar 

  18. Levine AG, Arvey A, Jin W, Rudensky AY (2014) Continuous requirement for the TCR in regulatory T cell function. Nat Immunol 15:1070–1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chaudhry A, Rudensky AY (2013) Control of inflammation by integration of environmental cues by regulatory T cells. J Clin Invest 123:939–944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vazquez G, Yurchenko E, Raissi TC, van der Windt GJ, Viollet B, Pearce EL, Pelletier J, Piccirillo CA, Krawczyk CM, Divangahi M, Jones RG (2015) The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 42:41–54

    Article  CAS  PubMed  Google Scholar 

  21. Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J, Workman CJ, Vignali DA (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501:252–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sharma MD, Shinde R, McGaha T, Huang L, Holmgaard RB, Wolchok JD, Mautino MR, Celis E, Sharpe A, Francisco LM, Powell DJ Jr, Yagita H, Mellor AL, Blazar BR, Munn DH (2015) The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Science Advances 1:e1500845

    Article  PubMed  PubMed Central  Google Scholar 

  23. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22:633–642

    Article  CAS  PubMed  Google Scholar 

  24. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176:6752–6761

    Article  CAS  PubMed  Google Scholar 

  25. Jewell JL, Russell RC, Guan KL (2013) Amino acid signalling upstream of mTOR. Nat Rev Molec Cell Biol 14:133–139

    Article  CAS  Google Scholar 

  26. Ye J, Palm W, Peng M, King B, Lindsten T, Li MO, Koumenis C, Thompson CB (2015) GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev 29:2331–2336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ravindran R, Loebbermann J, Nakaya HI, Khan N, Ma H, Gama L, Machiah DK, Lawson B, Hakimpour P, Wang YC, Li S, Sharma P, Kaufman RJ, Martinez J, Pulendran B (2016) The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 531:523–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Van de Velde LA, Guo XJ, Barbaric L, Smith AM, Oguin TH 3rd, Thomas PG, Murray PJ (2016) Stress kinase GCN2 controls the proliferative fitness and trafficking of cytotoxic T cells independent of environmental amino acid sensing. Cell reports 17:2247–2258

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ravishankar B, Liu H, Shinde R, Chaudhary K, Xiao W, Bradley J, Koritzinsky M, Madaio MP, McGaha TL (2015) The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity. Proc Natl Acad Sci USA 112:10774–10779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ravishankar B, Liu H, Shinde R, Chandler P, Baban B, Tanaka M, Munn DH, Mellor AL, Karlsson MC, McGaha TL (2012) Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc Natl Acad Sci USA 109:3909–3914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Peng W, Robertson L, Gallinetti J, Mejia P, Vose S, Charlip A, Chu T, Mitchell JR (2012) Surgical stress resistance induced by single amino acid deprivation requires Gcn2 in mice. Sci Transl Med 4:118ra11

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, Friedman L, Turner M, Okkenhaug K, Vanhaesebroeck B (2014) Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510:407–411

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Crellin NK, Garcia RV, Levings MK (2007) Altered activation of AKT is required for the suppressive function of human CD4+ CD25+ T regulatory cells. Blood 109:2014–2022

    Article  CAS  PubMed  Google Scholar 

  34. Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH, Bluestone JA, Turka LA (2015) Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 16:188–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kitz A, de Marcken M, Gautron AS, Mitrovic M, Hafler DA, Dominguez-Villar M (2016) AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease. EMBO Rep 17:1169–1183

    Article  CAS  PubMed  Google Scholar 

  36. Sharma MD, Huang L, Choi JH, Lee EJ, Wilson JM, Lemos H, Pan F, Blazar BR, Pardoll DM, Mellor AL, Shi H, Munn DH (2013) An inherently bifunctional subset of Foxp3 T helper cells is controlled by the transcription factor Eos. Immunity 38:998–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sharma MD, Hou DY, Baban B, Koni PA, He Y, Chandler PR, Blazar BR, Mellor AL, Munn DH (2010) Reprogrammed Foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33:942–954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sharma MD, Hou DY, Liu Y, Koni PA, Metz R, Chandler P, Mellor AL, He Y, Munn DH (2009) Indoleamine 2,3-dioxygenase controls conversion of Foxp3 + Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113:6102–6111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martinez-Llordella M, Ashby M, Nakayama M, Rosenthal W, Bluestone JA (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10:1000–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, Fehling HJ, Bluestone JA (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39:949–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hedrick SM, Hess Michelini R, Doedens AL, Goldrath AW, Stone EL (2012) FOXO transcription factors throughout T cell biology. Nat Rev Immunol 12:649–661

    Article  CAS  PubMed  Google Scholar 

  42. Kerdiles YM, Stone EL, Beisner DL, McGargill MA, Ch’en IL, Stockmann C, Katayama CD, Hedrick SM (2010) Foxo transcription factors control regulatory T cell development and function. Immunity 33:890–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206:3015–3029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, Azuma M, Blazar BR, Mellor AL, Munn DH (2007) Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117:2570–2582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Baban B, Chandler PR, Johnson BA 3rd, Huang L, Li M, Sharpe ML, Francisco LM, Sharpe AH, Blazar BR, Munn DH, Mellor AL (2011) Physiologic control of IDO competence in splenic dendritic cells. J Immunol 187:2329–2335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183:2475–2483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Huang L, Lemos HP, Li L, Li M, Chandler PR, Baban B, McGaha TL, Ravishankar B, Lee JR, Munn DH, Mellor AL (2012) Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells. J Immunol 188:4913–4920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, Yoshida R, Wakeham A, Higuchi T, Fukumoto M, Tsubata T, Ohashi PS, Koyasu S, Penninger JM, Nakano T, Mak TW (2001) T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14:523–534

    Article  CAS  PubMed  Google Scholar 

  49. Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP (1999) Impaired Fas response and autoimmunity in Pten ± mice. Science 285:2122–2125

    Article  PubMed  Google Scholar 

  50. Liu X, Karnell JL, Yin B, Zhang R, Zhang J, Li P, Choi Y, Maltzman JS, Pear WS, Bassing CH, Turka LA (2010) Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice. J Clin Invest 120:2497–2507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H (2015) Treg cells require the phosphatase PTEN to restrain Th1 and Tfh cell responses. Nat Immunol 16:178–187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. DuPage M, Chopra G, Quiros J, Rosenthal WL, Morar MM, Holohan D, Zhang R, Turka L, Marson A, Bluestone JA (2015) The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity 42:227–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kim HJ, Barnitz RA, Kreslavsky T, Brown FD, Moffett H, Lemieux ME, Kaygusuz Y, Meissner T, Holderried TA, Chan S, Kastner P, Haining WN, Cantor H (2015) Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science 350:334–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yang HY, Barbi J, Wu CY, Zheng Y, Vignali PD, Wu X, Tao JH, Park BV, Bandara S, Novack L, Ni X, Yang X, Chang KY, Wu RC, Zhang J, Yang CW, Pardoll DM, Li H, Pan F (2016) MicroRNA-17 modulates regulatory T cell function by targeting Co-regulators of the Foxp3 transcription factor. Immunity 45:83–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mak LH, Vilar R, Woscholski R (2010) Characterisation of the PTEN inhibitor VO-OHpic. J Chem Biol 3:157–163

    Article  PubMed  PubMed Central  Google Scholar 

  56. Heindl M, Händel N, Ngeow J, Kionke J, Wittekind C, Kamprad M, Rensing-Ehl A, Ehl S, Reifenberger J, Loddenkemper C, Maul J, Hoffmeister A, Aretz S, Kiess W, Eng C, Uhlig HH (2012) Autoimmunity, intestinal lymphoid hyperplasia, and defects in mucosal B-cell homeostasis in patients with PTEN hamartoma tumor syndrome. Gastroenterology 142(1093–6):e6

    Google Scholar 

  57. Spinelli L, Lindsay YE, Leslie NR (2015) PTEN inhibitors: an evaluation of current compounds. Adv Biol Regul 57:102–111

    Article  CAS  PubMed  Google Scholar 

  58. Munn DH, Mellor AL (2013) Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 34:137–143

    Article  CAS  PubMed  Google Scholar 

  59. Ravishankar B, Shinde R, Liu H, Chaudhary K, Bradley J, Lemos HP, Chandler P, Tanaka M, Munn DH, Mellor AL, McGaha TL (2014) Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proc Natl Acad Sci USA 111:4215–4220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Muller AJ, Duhadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11:312–319

    Article  CAS  PubMed  Google Scholar 

  61. Hou DY, Muller AJ, Sharma MD, Duhadaway JB, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH (2007) Inhibition of IDO in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with anti-tumor responses. Cancer Res 67:792–801

    Article  CAS  PubMed  Google Scholar 

  62. Li M, Bolduc AR, Hoda MN, Gamble DN, Dolisca SB, Bolduc AK, Hoang K, Ashley C, McCall D, Rojiani AM, Maria BL, Rixe O, MacDonald TJ, Heeger PS, Mellor AL, Munn DH, Johnson TS (2014) The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J Immunother Cancer (JITC) 2:21

    Article  CAS  Google Scholar 

  63. Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim CK, Tobias A, Cheng Y, Kim JW, Qiao J, Zhang L, Han Y, Lesniak MS (2014) Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res 20:5290–5301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Soliman HH, Minton SE, Han HS, Ismail-Khan R, Neuger A, Khambati F, Noyes D, Lush R, Chiappori AA, Roberts JD, Link C, Vahanian NN, Mautino M, Streicher H, Sullivan DM, Antonia SJ (2016) A phase I study of indoximod in patients with advanced malignancies. Oncotarget 7:22928–22938

    PubMed  PubMed Central  Google Scholar 

  65. Beatty GL, O’Dwyer PJ, Clark J, Shi JG, Bowman KJ, Scherle PA, Newton RC, Schaub R, Maleski J, Leopold L, Gajewski TF (2017) First-in-human phase 1 study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res. doi:10.1158/1078-0432.ccr-16-2272

    Google Scholar 

  66. Bahary N, Garrido-Laguna I, Cinar P, O’Rourke Ma, Somer BG, Nyak-Kapoor A, Lee JS, Munn DH, Kennedy EP, Vahanian NN, Link CJ, Wang-Gillam A (2016). Phase 2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: interim analysis. ASCO Annual Meeting Proceedings: (Abstract 3020)

  67. Johnson TS, Giller CA, Heger IM, Kennedy EP, Kolhe RB, Mourad WF, Rojiani AM, Sadek RF, Vahanian NN, Macdonald TJ, Munn DH (2016). Phase 1 trial of indoximod in combination with temozolomide-based therapy for children with progressive primary brain tumors (NCT02502708). Pediatr Blood Cancer 63(Suppl. 1):S72-S3. Abstract from the 29th Annual Meeting of the American Society of Pediatric Hematology/Oncology (ASPHO), Minneapolis MN, May 2016

  68. Zakharia Y, Munn D, Link C, Vahanian N, Kennedy E (2016). Interim analysis of Phase 1b/2 combination of the IDO pathway inhibitor indoximod with temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors. Neuro-Oncology 18(suppl. 6):vi13-4. Abstract from the 21st Annual Meeting of the Society for Neuro-Oncology (SNO), Scottsdale AZ, November 2016

  69. Nardella C, Clohessy JG, Alimonti A, Pandolfi PP (2011) Pro-senescence therapy for cancer treatment. Nat Rev Cancer 11:503–511

    Article  CAS  PubMed  Google Scholar 

  70. Hodi FS, Hwu WJ, Kefford R, Weber JS, Daud A, Hamid O, Patnaik A, Ribas A, Robert C, Gangadhar TC, Joshua AM, Hersey P, Dronca R, Joseph R, Hille D, Xue D, Li XN, Kang SP, Ebbinghaus S, Perrone A, Wolchok JD (2016) Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 34:1510–1517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Munn DH, Mellor AL (2016) IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 37:193–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Supported in part by Grants CA096651 and CA103320 from the National Institutes of Health, and the Beloco foundation.

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Authors and Affiliations

  1. Georgia Cancer Center, Medical College of Georgia, Augusta University, Room CN4141, Augusta, GA, 30912, USA

    David H. Munn, Madhav D. Sharma, Theodore S. Johnson & Paulo Rodriguez

  2. Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    David H. Munn, Madhav D. Sharma & Theodore S. Johnson

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  1. David H. Munn
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  2. Madhav D. Sharma
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Correspondence to David H. Munn.

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Conflict of interest

David Munn is a consultant to NewLink Genetics Corporation and holds intellectual property in IDO-inhibitors and PTEN-inhibitors. Theodore Johnson receives funding for clinical trials of IDO-inhibitors from NewLink Genetics, Inc. The authors declare that there are no other conflicts of interest.

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This paper is a Focussed Research Review based on a presentation given at the conference Regulatory Myeloid Suppressor Cells: From Basic Discovery to Therapeutic Application which was hosted by the Wistar Institute in Philadelphia, PA, USA, 16th–19th June, 2016. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews.

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Munn, D.H., Sharma, M.D., Johnson, T.S. et al. IDO, PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment. Cancer Immunol Immunother 66, 1049–1058 (2017). https://doi.org/10.1007/s00262-017-2010-2

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