Small-Molecule Targets in Immuno-Oncology

Cell Chemical Biology

Volumn 24, Issue 9, 2017, Pages 1148-1160

  Dhanak, Dashyant ^a   Edwards, James P ^a   Nguyen, Ancho ^a   Tummino, Peter J ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

A2A PROTEIN; A2B PROTEIN; ANTINEOPLASTIC AGENT; BIOLOGICAL PRODUCT; RORGT PROTEIN; SMALL MOLECULE TRANSPORT AGENT; STING PROTEIN; TOLL LIKE RECEPTOR; TUMOR PROTEIN; UNCLASSIFIED DRUG; CTLA4 PROTEIN, HUMAN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; IMMUNOLOGIC FACTOR; MEMBRANE PROTEIN; MPYS PROTEIN, HUMAN; PDCD1 PROTEIN, HUMAN; PROGRAMMED DEATH 1 RECEPTOR; RETINOID RELATED ORPHAN RECEPTOR GAMMA;

ADAPTIVE IMMUNITY; CANCER IMMUNOLOGY; CANCER IMMUNOTHERAPY; HUMAN; IMMUNOPOTENTIATION; INNATE IMMUNITY; LYMPHOCYTE ACTIVATION; MOLECULARLY TARGETED THERAPY; NONHUMAN; OVERALL SURVIVAL; PRIORITY JOURNAL; REVIEW; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECT; DRUG THERAPY; IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; MOLECULAR LIBRARY; NEOPLASM; PHARMACOLOGY;

CTLA-4 ANTIGEN; HUMANS; IMMUNOLOGIC FACTORS; IMMUNOTHERAPY; LYMPHOCYTE ACTIVATION; MEMBRANE PROTEINS; NEOPLASMS; NUCLEAR RECEPTOR SUBFAMILY 1, GROUP F, MEMBER 3; PROGRAMMED CELL DEATH 1 RECEPTOR; SMALL MOLECULE LIBRARIES; TOLL-LIKE RECEPTORS;

EID: 85029624705     PISSN: 24519456     EISSN: 24519448     Source Type: Journal    
DOI: 10.1016/j.chembiol.2017.08.019     Document Type: Review

References (139)

1. Adams, J.L., Smothers, J., Srivivasan, R., Hoos, A., Big opportunities for small molecules in immune-oncology. Nat. Rev. Drug Discov. 14 (2015), 603–622.
2. Aldarouish, M., Wang, C., Trends and advances in tumor immunology and lung cancer immunotherapy. J. Exp. Clin. Cancer Res. 35 (2016), 1–13.
3. Allison, J.P., Checkpoints. Cell 162 (2015), 1202–1205.
4. Arrowsmith, C.H., Bountra, C., Fish, P.V., Lee, K., Schapira, M., Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discov. 11 (2012), 384–400.
5. Baguley, B.C., Ching, L.M., Immunomodulatory actions of xanthenone anticancer agents. BioDrugs 8 (1997), 119–127.
6. Baird, J.R., Friedman, D., Cottam, B., Dubensky, T.W. Jr., Kanne, D.B., Bambina, S., Bahjat, K., Crittenden, M.R., Gough, M.J., Radiotherapy combined with novel STING-targeting oligonucleotides results in regression of established tumors. Cancer Res. 76 (2016), 50–61.
7. Basile, D., Garattini, S.K., Bonotto, M., Ongaro, E., Casagrande, M., Cattaneo, M., Fanotto, V., Carlo, E.D., Loupakis, F., Urbano, F., et al. Immunotherapy for colorectal cancer: where are we heading?. Expert Opin. Biol. Ther. 17 (2017), 709–721.
8. Beavis, P.A., Stagg, J., Darcy, P.K., Smyth, M.J., CD73: a potent suppressor of antitumor immune responses. Trends Immunol. 33 (2012), 231–237.
9. Beavis, P.A., Divisekera, U., Paget, C., Chow, M.T., John, L.B., Devaud, C., Dwyer, K., Stagg, J., Smyth, M.J., Darcy, P.K., Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc. Natl. Acad. Sci. USA 110 (2013), 14711–14716.
10. Berthon, C., Fontenay, M., Corm, S., Briche, I., Allorge, D., Hennart, B., Lhermitte, M., Quesnel, B., Metabolites of tryptophan catabolism are elevated in sera of patients with myelodysplastic syndromes and inhibit hematopoietic progenitor amplification. Leuk. Res. 37 (2013), 573–579.
11. Blay, J., White, T.D., Hoskin, D.W., The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 57 (1997), 2602–2605.
12. Brandacher, G., Perathoner, A., Ladurner, R., Schneeberger, S., Obrist, P., Winkler, C., Werner, E.R., Werner-Felmayer, G., Weiss, H.G., G√∂bel, G., et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin. Cancer Res. 12 (2006), 1144–1151.
13. Brochez, L., Chevolet, I., Kruse, V., The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur. J. Cancer 76 (2017), 167–182.
14. Bronner, S.M., Zbieg, J.R., Crawford, J.J., RORγ antagonists and inverse agonists: a patent review. Exp. Opin. Ther. Pat. 27 (2017), 101–112.
15. Burdette, D.L., Vance, R.E., STING and the innate immune response to nucleic acids in the cytosol. Nat. Immunol. 14 (2013), 19–26.
16. Callahan, M.K., Postow, M.A., Wolchok, J.D., Targeting T cell co-receptors for cancer therapy. Immunity 44 (2016), 1069–1078.
17. Campbell, L., Saville, C.R., Murray, P.J., Cruickshank, S.M., Hardman, M.J., Local arginase 1 activity is required for cutaneous wound healing. J. Invest. Dermatol. 133 (2013), 2461–2470.
18. Chang, M.R., Dharmarajan, V., Doebelin, C., Garcai-Ordonez, R.D., Novick, S.J., Kuruvilla, D.S., Kamenecka, T.M., Griffin, P.R., Synthetic RORγt agonists enhance protective immunity. ACS Chem. Biol. 11 (2016), 1012–1018.
19. Chen, D.S., Mellman, I., Elements of cancer immunity and the cancer-immune set point. Nature 541 (2017), 321–330.
20. Coley, W.B., Contribution to the knowledge of sarcoma. Ann. Surg. 14 (1891), 199–220.
21. Conlon, J., Burdette, D.L., Sharma, S., Bhat, N., Thompson, M., Jiang, Z., Rathinam, V.A.K., Monks, B., Jin, T., Xiao, T.S., et al. Mouse, but not human, STING binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J. Immunol. 190 (2013), 5216–5225.
22. Corrales, L., Glickman, L.H., McWhirter, S.M., Kanne, D.B., Sivick, K.E., Katibah, G.E., Woo, S.-R., Lemmens, E., Banda, T., Leong, J.J., et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11 (2015), 1018–1030.
23. Corrales, L., McWhirter, S.M., Dubensky, T.W. Jr., Gajewski, T.F., The host STING pathway at the interface of cancer and immunity. J. Clin. Invest. 126 (2016), 2404–2411.
24. Cristalli, G., Lambertucci, G., Volpini, R., Dal Ben, D., A2A adenosine receptor and its modulators: overview on a druggable GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonist. Curr. Pharm. Des. 14 (2008), 1525–1552.
25. Curran, E., Chen, X., Corrales, L., Kline, D.E., Dubensky, T.W. Jr., Duttagupta, P., Kortylewski, M., Kline, J., STING pathway activation stimulates potent immunity against acute myeloid leukemia. Cell Rep. 15 (2016), P2357–P2366.
26. Cyr, P., Bronner, S.M., Crawford, J.J., Recent progress on nuclear receptor RORγ modulators. Bioorg. Med. Chem. Lett. 26 (2016), 4387–4393.
27. Dietsch, G.N., Randall, T.D., Gottardo, R., Northfelt, D.W., Ramanathan, R.K., Cohen, P.A., Manjarrez, K.L., Newkirk, M., Bryan, J.K., Hershberg, R.M., Late-stage cancer patients remain highly responsive to immune activation by the selective TLR8 agonist motolimod (VTX-2337). Clin. Cancer Res. 21 (2015), 5445–5452.
28. Dietsch, G.N., Lu, H., Yang, Y., Morishima, C., Chow, L.Q., Disis, M.L., Hershberg, R.M., Coordinated activation of Toll-like receptor 8 (TLR8) and NLRP3 by the TLR8 agonist, VTX-2337, ignites tumoricidal natural killer cell activity. PLoS One 11 (2016), 1–18.
29. Disis, M.L., Stanton, S.E., Immunotherapy in breast cancer: an introduction. Breast, 2017, 10.1016/j.breast.2017.01.013.
30. Fauber, B.P., Magnuson, S., Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc). J. Med. Chem. 57 (2014), 5871–5892.
31. Floyd, M., El Osta, B., Tang, S.-C., First report of parkinsonism associated with indoximod, an immune-modulating agent. J. Glob. Oncol., 2016, 10.1200/JGO.2016.007492.
32. Gabrilovich, D.I., Myeloid-derived suppressor cells. Cancer Immunol. Res. 5 (2017), 3–8.
33. Gabrilovich, D.I., Nagaraj, S., Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9 (2009), 162–174.
34. Gao, D., Li, T., Li, X.-D., Chen, X., Li, Q.-Z., Wight-Carter, M., Chen, Z.J., Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc. Natl. Acad. Sci. USA 112 (2015), E5699–E5705.
35. Gao, P., Ascano, M., Zillinger, T., Wang, W., Dai, P., Serganov, A.A., Gaffney, B.L., Shuman, S., Jones, R.A., Deng, L., et al. Structure-function analysis of STING activation by c[G(2’,5’)pA(3’,5’)p] and targeting by antiviral DMXAA. Cell 154 (2015), 748–762.
36. Glickman, L.H., Kanne, D.B., Kasibhatla, S., Li, J., Pferdekamper, A.C., Gauthier, K.S., Deng, W., Desbien, A.L., Katibah, G.E., Leong, J.J., et al. STING activation in the tumor microenvironment with a synthetic human STING-activating cyclic dinucleotide leads to potent anti-tumor immunity. Cancer Res., 76, 2016 Abstract 1445.
37. Guha, M., Anticancer TLR agonists on the ropes. Nat. Rev. Drug Discov. 11 (2012), 503–505.
38. Gutierrez-de-Teran, H., Sallander, J., Sotelo, E., Structure-based rational design of adenosine receptor ligands. Curr. Top. Med. Chem. 17 (2017), 40–58.
39. Gyulveszi, G., Fischer, C., Mirolo, M., Stern, M., Green, L., Ceppi, M., Wang, H., Bergi, B., Staempfli, A., Muster, W., et al. RG70099: a novel, highly potent dual IDO1/TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment. Cancer Res., 2016, 10.1158/1538-7445.AM2016-LB-085 Abstract LB-085.
40. Hatfield, S.M., Sitkovsky, M., A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr. Opin. Pharmacol. 29 (2016), 90–96.
41. Hellmann, M.D., Rizvi, N.A., Goldman, J.W., Gettinger, S.N., Borghaei, H., Brahmer, J.R., Ready, N.E., Gerber, D.E., Chow, L.Q., Juergens, R.A., et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 18 (2017), 31–41.
42. Hemmi, H., Kaisho, T., Takeuchi, O., Sato, S., Sanjo, H., Hoshino, K., Horiuchi, T., Tomizawa, H., Takeda, H., Takeda, K., et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3 (2002), 196–200.
43. Hennessy, E.J., Parker, A.E., O'Neill, L.A.J., Targeting Toll-like receptors: emerging therapeutics?. Nat. Rev. Drug Discov. 9 (2010), 293–307.
44. Hickey, P., Stacy, M., Adenosine A2A antagonists in Parkinson's disease: what's next?. Curr. Neurol. Neurosci. Rep. 12 (2012), 376–385.
45. Hu, X., Liu, X., Moisan, J., Wang, Y., Lesch, C.A., Spooner, C., Morgan, R.W., Zawidzka, E.M., Mertz, D., Bousley, D., et al. Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity. Oncoimmunology, 5, 2016, e1254854.
46. Hugo, W., Zaretsky, J.M., Sun, L., Song, C., Moreno, B.H., Hu-Lieskovan, S., Berent-Maoz, B., Pang, J., Chmielowski, B., Cherry, G., et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 24 (2016), 35–44.
47. Ino, K., Yamamoto, E., Shibata, K., Kajiyama, H., Yoshida, N., Terauchi, M., Nawa, A., Nagasaka, T., Takikawa, O., Kikkawa, F., Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin. Cancer Res. 14 (2008), 2310–2317.
48. Iribarren, K., Bloy, N., Buqué, A., Cremer, I., Eggermont, A., Hervé Fridman, W., Fucikova, J., Galon, J., Špíšek, R., Zitvogel, L., et al. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy. Oncoimmunology, 5, 2016, 10.1080/2162402X.2015.1088631.
49. + T helper cells. Cell 126 (2006), 1121–1133.
50. Iyer, V.V., Small molecules for immunomodulation in cancer: a review. Anticancer Agents Med. Chem. 15 (2015), 433–452.
51. Jacobsen, K.A., Muller, C.E., Medicinal chemistry of adenosine, P2Y, and P2X receptors. Neuropharmacology 104 (2016), 31–49.
52. Jassar, A.S., Suzuki, E., Kapoor, V., Sun, J., Silverberg, M.B., Cheung, L., Burdick, M.D., Stieter, R.M., Ching, L.M., Kaiser, L.R., Albelda, S.M., Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxantheone-4-acetic acid induces an effective CD8+ T-cell mediated antitumor immune response in murine models of lung cancer and mesothelioma. Cancer Res. 65 (2005), 11752–11761.
53. Jazayeri, A., Andrews, S.P., Marshall, F.H., Structurally-enabled discovery of adenosine A2A receptor antagonists. Chem. Rev. 117 (2017), 21–37.
54. Jetten, A.M., Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl. Recept. Signal. 7 (2009), 1–32.
55. Jin, M.S., Lee, J.-O., Structures of the Toll-like receptor family and its ligand complexes. Immunity 29 (2008), 182–191.
56. Johnson, D.B., Balko, J.M., Compton, M.L., Chalkias, S., Gorham, J., Yaomin, X., Hicks, M., Puzanov, I., Alexander, M.R., Bloomer, T.L., et al. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375 (2016), 1749–1755.
57. Joyce, J.A., Fearon, D.T., T cell exclusion, immune privilege, and the tumor microenvironment. Science 348 (2015), 74–80.
58. June, C.H., Warshauer, J.T., Bluestone, J.A., Is autoimmunity the Achilles' heel of cancer immunotherapy?. Nat. Med. 23 (2017), 540–547.
59. Kaczanowska, S., Joseph, A.M., Davila, E., TLR agonists: our best frenemy in cancer immunotherapy. J. Leukoc. Biol. 93 (2013), 847–863.
60. Kawai, T., Akira, S., The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11 (2011), 373–384.
61. Khanna, P., Blais, N., Gaudreau, P.-O., Corrales-Rodriguez, L., Immunotherapy comes of age in lung cancer. Clin. Lung Cancer 18 (2017), 13–22.
62. Kojetin, D.J., Burris, T.P., REV-ERB and ROR nuclear receptors as drug targets. Nat. Rev. Drug Discov. 13 (2014), 197–216.
63. Krieg, A.M., Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27 (2008), 161–167.
64. Langer, C., Gaddgeel, S.M., Borghaei, H., Papadimitrakopoulou, V.A., Patnaik, A., Powell, S., Gentzler, R.D., Martins, R.D., Stevenson, J.P., Jalal, S.I., et al. Randomized, phase 2 study of carboplatin and pemetrexed with or without pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G. Ann. Oncol., 27, 2016, LBA46_PR.
65. Leifer, C.A., Rose, W.A., Botelho, F., Traditional biochemical assays for studying Toll-like receptor 9. J. Immunoassay Immunochem. 34 (2013), 1–15.
66. Leone, R.D., Lo, Y.-C., Powell, J.D., A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comp. Struct. Biotechnol. J. 13 (2015), 265–272.
67. Leprieur, G.E., Dumenil, C., Julie, C., Giraud, V., Dumoulin, J., Labrune, S., Chinet, T., Immunotherapy revolutionises non-small-cell lung cancer therapy: results, perspectives and new challenges. Eur. J. Cancer 78 (2017), 16–23.
68. Liu, X., Wang, C., The emerging roles of the STING adaptor protein in immunity and diseases. Immunology 147 (2015), 285–291.
69. bhighIalow regulatory dendritic cells suppress T cell response through arginase 1. J. Immunol. 182 (2009), 6207–6216.
70. Lu, H., Dietsch, G.N., Matthews, M.-A., Yang, Y., Ghanekar, S., Inokuma, M., Suni, M., Maino, V.C., Henderson, K.E., Howbert, J.J., et al. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin. Cancer Res. 18 (2012), 499–509.
71. Mahoney, K.M., Rennert, P.D., Freeman, G.J., Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14 (2015), 561–581.
72. Malhotra, J., Jabbour, S.K., Aisner, J., Current state of immunotherapy for non-small cell lung cancer. Transl. Lung Cancer Res. 6 (2017), 196–211.
73. Manera, C., Saccomanni, G., A2A receptor ligands: past, present and future trends. Curr. Top. Med. Chem. 10 (2010), 909–922.
74. Metz, R., DuHadaway, J.B., Kamasani, U., Laury-Kleintop, L., Muller, A.J., Prendergast, G.C., Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 67 (2007), 7082–7087.
75. Mittal, D., Young, A., Stannard, K., Yong, M., Teng, M.W.L., Allard, B., Stagg, J., Smyth, M.J., Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74 (2014), OF1–OF7.
76. Molon, B., Ugel, S., Del Pozzo, F., Soldani, C., Zilio, S., Avella, D., De Palma, A., Mauri, P.L., Monegal, A., Rescigno, M., et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J. Exp. Med. 208 (2011), 1949–1962.
77. Muller, A.I., DuHadaway, J.B., Donover, P.S., Sutanto-Ward, E., Prendergast, G.C., Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med. 11 (2005), 312–319.
78. Munn, D.H., Zhou, M., Attwood, J.T., Bondarev, I., Conway, S.J., Marshall, B., Brown, C., Mellor, A.L., Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281 (1998), 1191–1193.
79. Nagaraj, S., Gupta, K., Pisarev, V., Kinarsky, L., Sherman, S., Kang, L., Herber, D.L., Schneck, J., Gabrilovich, D.I., Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 13 (2007), 828–835.
80. O'Neill, L.A., Golenbock, D., Bowie, A.G., The history of Toll-like receptors – redefining innate immunity. Nat. Rev. Immunol. 13 (2013), 453–460.
81. Ohta, A., A metabolic immune checkpoint: adenosine in the tumor microenvironment. Front. Immunol. 7 (2016), 1–11.
82. Ohta, A., Gorelik, E., Prasad, S.J., Ronchese, F., Lukashev, D., Wong, M.K.K., Huang, X., Caldwell, S., Liu, K., Smith, P., et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl. Acad. Sci. USA 103 (2006), 13132–13137.
83. Ohto, U., Tanji, H., Shimizu, T., Structure and function of toll-like receptor 8. Microbes Infect. 16 (2014), 273–282.
84. Ohto, U., Shibata, T., Tanji, H., Ishida, H., Krayukhina, E., Uchiyama, S., Miyake, K., Shimizu, T., Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9. Nature 520 (2015), 702–705.
85. Papadopoulos, K.P., Tsai, F.Y.-C., Bauer, T.M., Muigai, L., Liang, Y., Bennett, M.K., Orford, K.W., Fu, S., CX-1158-101: a first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients (pts) with solid tumors. J. Clin. Oncol., 35, 2017, 3005.
86. Perera, P.Y., Barber, S.A., Ching, L.M., Vogel, S.N., Activation of LPS-inducible genes by the antitumor agent 5,6-dimethylxanthenone-4-acetic acid in primary murine macrophages. J. Immunol. 153 (1994), 4684–4693.
87. Pfirschke, C., Engblom, C., Rickelt, S., Cortez-Retamozo, V., Garris, C., Pucci, F., Yamazaki, T., Poirier-Colame, V., Newton, A., Redouane, Y., et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 16 (2016), 343–354.
88. Pilotte, L., Larrieu, P., Stroobant, V., Colau, D., Dolušić, E., Frédérick, R., De Plaen, E., Uyttenhove, C., Wouters, J., Masereel, B., et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl. Acad. Sci. USA 109 (2012), 2497–2502.
89. Pinna, A., Adenosine A2A receptor antagonists in Parkinson's disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs 28 (2014), 455–474.
90. Platten, M., Wick, W., Van den Eynde, B.J., Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 72 (2012), 5435–5440.
91. Postow, M.A., Callahan, M.K., Wolchok, J.D., Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33 (2015), 1974–1982.
92. Prantner, D., Perkins, D.J., Lai, W., Williams, M.S., Sharma, S., Fitzgerald, K.A., Vogel, S.N., 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential. J. Bio Chem. 287 (2012), 39776–39788.
93. Prima, V., Kaliberova, L.N., Kaliberov, S., Curiel, D.T., Kusmartsev, S., COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc. Natl. Acad. Sci. USA 114 (2017), 1117–1122.
94. Remon, J., Besse, B., Immune checkpoint inhibitors in first-line therapy of advanced non-small cell lung cancer. Curr. Opin. Oncol. 29 (2017), 97–104.
95. Remon, J., Pardo, N., Martinez-Martí, A., Cedrés, S., Navarro, A., Martinez de Castro, A.M., Felip, E., Immune-checkpoint inhibition in first-line treatment of advanced non-small cell lung cancer patients: current status and future approaches. Lung Cancer 106 (2017), 70–75.
96. Rene, O., Fauber, B.P., Boenig, G., Burton, B., Eidenschenk, C., Everett, C., Gobbi, A., Hymowitz, S.G., Johson, A.R., Kiefer, J.R., et al. Minor structural change to tertiary sulfonamide RORc ligands led to opposite mechanisms of action. ACS Med. Chem. Lett. 6 (2015), 276–281.
97. Rodero, M.P., Crow, Y.J., cGMP-AMP synthase paves the way to autoimmunity. Proc. Natl. Acad. Sci. USA 112 (2015), 12903–12904.
98. Rodriguez, P.C., Hernandez, C.P., Quiceno, D., Dubinett, S.M., Zabaleta, J., Ochoa, J.B., Gilbert, J., Ochoa, A.C., Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J. Exp. Med. 202 (2005), 931–939.
99. Rodriguez, P.C., Ochoa, A.C., Al-Khami, A.A., Arginine metabolism in myeloid cells shapes innate and adaptive immunity. Front. Immunol. 8 (2017), 1–12.
100. Roh, W., Chen, P.L., Reuben, A., Spencer, C.N., Prieto, P.A., Miller, J.P., Gopalakrishnan, V., Wang, F., Cooper, Z.A., Reddy, S.M., et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci. Transl. Med., 9, 2017, eaah3560.
101. Rohrig, U.F., Majjigapu, S.M., Vogel, P., Zoete, V., Michielin, O., Challenges in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. J. Med. Chem. 58 (2015), 9421–9437.
102. Rubin, A.I., Chen, E.H., Ratner, D., Basal-cell carcinoma. N. Engl. J. Med. 353 (2005), 2262–2269.
103. Rukovets, O., Why did preladenant for Parkinson's fail in the phase 3 trial?. Neurol. Today 14 (2014), 12–15.
104. Rutz, S., Eidenschenk, C., Kiefer, J.R., Ouyang, W., Post-translational regulation of RORgt – a therapeutic target for the modulation of interleukin-17-mediated responses in autoimmune disease. Cytokine Growth Factor Rev. 30 (2016), 1–17.
105. Schmidt, C., Clinical setbacks for toll-like receptor 9 agonists in cancer. Nat. Biotechnol. 25 (2007), 825–826.
106. Shang, G., Zhu, D., Li, N., Zhang, J., Zhu, C., Lu, D., Liu, C., Yu, Q., Zhao, Y., Xu, S., et al. Crystal structures of STING protein reveal basis of recognition of cyclic di-GMP. Nat. Struct. Mol. Biol. 19 (2012), 725–728.
107. Sharma, P., Allison, J.P., The future of immune checkpoint therapy. Science 348 (2015), 56–61.
108. Shin, D.S., Zaretsky, J.M., Escuin-Ordinas, H., Garcia-Diaz, A., Hu-Lieskovan, S., Kalbasi, A., Grasso, C.S., Hugo, W., Sandoval, S., Torrejon, D.Y., et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 7 (2017), 188–201.
109. Simon and Bromberg. (2016). https://www.ncbi.nlm.nih.gov/pubmed/27851922.
110. Snyder, A., Zamarin, D., Wolchok, J.D., Immunotherapy of melanoma. Prog. Tumor Res. 42 (2015), 22–29.
111. Soliman, H.H., Jackson, E., Neuger, T., Dees, E.C., Harvey, R.D., Han, H., Ismail-Khan, R., Minton, S., Vahanian, N.N., Link, C., et al. A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors. Oncotarget 5 (2014), 8136–8146.
112. Soliman, H.H., Minton, S.E., Han, H.S., Ismail-Khan, R., Neuger, A., Khambati, F., Noyes, D., Lush, R., Chiappori, A.A., Roberts, J.D., et al. A phase I study of indoximod in patients with advanced malignancies. Oncotarget 7 (2016), 22928–22938.
113. Solt, L.A., Griffin, P.R., Burris, T.P., Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics. Curr. Opin. Lipidol. 21 (2010), 204–211.
114. Solt, L.A., Kumar, N., Nuhant, P., Wang, Y., Lauer, J.L., Liu, J., Istrate, M.A., Kamenecka, T.M., Roush, W.R., Vidovic, D., et al. Suppression of Th17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472 (2011), 491–494.
115. Sorrentino, R., Pinto, A., Morello, S., The adenosinergic system in cancer: key therapeutic target. Oncoimmunology, 2, 2013, e22448.
116. Spranger, S., Luke, J.J., Bao, R., Zha, Y., Hernandez, K.M., Li, Y., Gajewski, A.P., Andrade, J., Gajewski, T.F., Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc. Natl. Acad. Sci. USA 113 (2016), E7759–E7768.
117. Spranger, S., Dai, D., Horton, B., Gajewski, T.F., Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 8 (2017), 711–723.
118. Steggerda, S., Bennett, M., Chen, J., Emberley, E., Gross, M., Huang, T., Li, W., MacKinnon, A., Makkouk, A., Marguier, G., et al. (2016). Arginase inhibitor CB-1158 is a novel immuno-oncology agent that targets tumor-infiltrating suppressive myeloid cells. EORTC-NCI-AACR Symposium, Munich, Germany. November 29-December 2, 2016.
119. Sullivan, R.J., Flaherty, K.T., Immunotherapy: anti-PD-1 therapies - a new first-line option in advanced melanoma. Nat. Rev. Clin. Oncol. 12 (2015), 625–626.
120. Sullivan, R.J., Flaherty, K.T., Pembrolizumab for treatment of patients with advanced or unresectable melanoma. Clin. Cancer Res. 21 (2015), 2892–2897.
121. Tanji, H., Ohto, U., Shibata, T., Miyake, K., Shimizu, T., Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. Science 339 (2013), 1426–1429.
122. Testerman, T.L., Gerster, J.F., Imbertson, L.M., Reiter, M.J., Miller, R.L., Gibson, S.J., Wagner, T.L., Tomai, M.A., Cytokine induction by the immunomodulators imiquimod and S-27609. J. Leukoc. Biol. 58 (1995), 865–872.
123. Topalian, S.L., Drake, C.G., Pardoll, D.M., Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27 (2015), 451–461.
124. Tumeh, P.C., Harview, C.L., Yearley, J.H., Shintaku, P.I., Taylor, E.J.M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515 (2014), 568–571.
125. Wainwright, D.A., Balyasnikova, I.V., Chang, A.L., Ahmed, A.U., Moon, K.-S., Auffinger, B., Tobias, A.L., Han, Y., Lesniak, M.S., IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin. Cancer Res. 18 (2012), 6110–6121.
126. Wang, H.-F., Ning, F., Liu, Z.-C., Wu, L., Li, Z.-Q., Qi, Y.-F., Zhang, G., Wang, H.-S., Cai, H.-S., Du, J., Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro. Cancer Immunol. Immunother. 66 (2017), 355–366.
127. Weeks, C.E., Gibson, S.J., Induction of interferon and other cytokines by imiquimod and its hydroxylated metabolite R-842 in human blood cells in vitro. J. Interferon Res. 14 (1994), 81–85.
128. Weihrauch, M.R., Richly, H., von Bergwelt-Baildon, M.S., Becker, H.J., Schmidt, M., Hacker, U.T., Shimabukuro-Vornhagen, A., Holtick, U., Nokay, B., Schroff, M., et al. Phase I clinical study of toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumors. Euro J. Cancer 51 (2015), 146–156.
129. Weinmann, H., Cancer immunotherapy: selected targets and small-molecule modulators. ChemMedChem 11 (2016), 450–466.
130. Wittig, B., Schmidt, M., Scheithauer, W., Schmoll, H.-J., MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: from bench to bedside. Crit. Rev. Oncol. Hematol. 94 (2015), 31–44.
131. Woo, S.R., Corrales, L., Gajewski, T.F., Innate immune recognition of cancer. Annu. Rev. Immunol. 33 (2015), 445–474.
132. Wu, J.-S., Lin, S.-Y., Liao, F.-Y., Hsiao, W.-C., Lee, L.-C., Peng, Y.-H., Hsieh, C.-L., Wu, M.-H., Song, J.-S., Yueh, A., et al. Identification of substituted naphthotriazolediones as novel tryptophan 2,3-dioxygenase (TDO) inhibitors through structure-based virtual screening. J. Med. Chem. 58 (2015), 7807–7819.
133. Yin, Q., Tian, Y., Kabaleeswaran, V., Jiang, X., Tu, D., Eck, M.J., Chen, Z.J., Wu, H., Cyclic di-GMP sensing via the innate immune signaling protein STING. Mol. Cell 46 (2012), 735–745.
134. Youn, J.-I., Kumar, V., Collazo, M., Nefedova, Y., Condamine, T., Cheng, P., Villagra, A., Antonia, S., McCaffrey, J.C., Fishman, M., et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat. Immunol. 14 (2013), 211–222.
135. Yue, E.W., Douty, B., Wayland, B., Bower, M., Liu, X., Leffet, L., Wang, Q., Bowman, K.J., Hansbury, M.J., Changnian Liu, C., et al. Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J. Med. Chem. 52 (2009), 7364–7367.
136. Yue, E.W., Sparks, R., Polam, P., Modi, D., Douty, B., Wayland, B., Glass, B., Takvorian, A., Glenn, J., Wenyu Zhu, W., et al. INCB24360 (Epacadostat), a highly potent and selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor for immunooncology. ACS Med. Chem. Lett. 8 (2017), 486–491.
137. Zaretsky, J.M., Garcia-Diaz, A., Shin, D.S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D.Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L., et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375 (2016), 819–829.
138. Zhang, Z., Ohto, U., Shibata, T., Krayukhina, E., Taoka, M., Yamauchi, Y., Tanji, H., Isobe, T., Uchiyama, S., Miyake, K., Shimizu, T., Structural analysis reveals that Toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA. Immunity 45 (2016), 737–748.
139. Zhang, Q., Chikina, M., Szymczak-Workman, A.L., Horne, W., Kolls, J.K., Vignali, K.M., Normolle, D., Bettini, M., Workman, C.J., Vignali, D.A.A., LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci. Immunol., 31, 2017, eaah4569.