Big opportunities for small molecules in immuno-oncology

Nature Reviews Drug Discovery

Volumn 14, Issue 9, 2015, Pages 603-621

  Adams, Jerry L ^a   Smothers, James ^a   Srinivasan, Roopa ^a   Hoos, Axel ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINO N (3 CHLORO 4 FLUOROPHENYL) N' HYDROXY 1,2,5 OXADIAZOLE 3 CARBOXIMIDAMIDE; 5 AMINO 2 (2 FURYL) 7 (2 PHENYLETHYL)PYRAZOLO[4,3 E][1,2,4]TRIAZOLO[1,5 C]PYRIMIDINE; ACETYLSALICYLIC ACID 3 (NITROXYMETHYL)PHENYL ESTER; ADENOSINE TRIPHOSPHATE; AGATOLIMOD; ALPHA,BETA METHYLENEADENOSINE DIPHOSPHATE; CARBOPLATIN; CELECOXIB; DABRAFENIB; DEFOSLIMOD; GALUNISERTIB; IMIQUIMOD; INDOXIMOD; IPILIMUMAB; ISTRADEFYLLINE; LEFITOLIMOD; MARAVIROC; MONOCLONAL ANTIBODY; MOTOLIMOD; N [4 [(2 AMINO 3 CHLORO 4 PYRIDINYL)OXY] 3 FLUOROPHENYL] 4 ETHOXY 1 (4 FLUOROPHENYL) 2(1H) OXONICOTINAMIDE; NIVOLUMAB; PACLITAXEL; PEMBROLIZUMAB; PF 4136309; PLERIXAFOR; PRELADENANT; SIPULEUCEL T; TADALAFIL; UNINDEXED DRUG; VEMURAFENIB;

AMINO ACID METABOLISM; BASAL CELL CARCINOMA; CANCER IMMUNOTHERAPY; COLON CANCER; COLORECTAL CARCINOMA; DRUG EFFICACY; DRUG SELECTIVITY; DRUG TARGETING; ENZYME INHIBITION; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HEMATOLOGIC MALIGNANCY; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOMODULATION; IMMUNOREGULATION; KIDNEY CARCINOMA; LUNG CANCER; MELANOMA; METASTASIS; METASTATIC COLORECTAL CANCER; METASTATIC MELANOMA; NON SMALL CELL LUNG CANCER; NONHUMAN; OSTEOARTHRITIS; PAIN; PANCREAS ADENOCARCINOMA; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; REVIEW; RHEUMATOID ARTHRITIS; SOLID TUMOR; T LYMPHOCYTE ACTIVATION; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; ANIMAL; DRUG EFFECTS; IMMUNOLOGY; IMMUNOTHERAPY; NEOPLASMS; TRENDS;

ANIMALS; ANTIBODIES, MONOCLONAL; HUMANS; IMMUNOTHERAPY; NEOPLASMS; TUMOR MICROENVIRONMENT;

EID: 84940890382     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4596     Document Type: Review

References (133)

1. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539-545 (2001).
2. Coley, W. B. Contribution to the knowledge of sarcoma. Ann. Surg. 14, 199-220 (1891).
3. Cheever, M. A. & Higano, C. S. Provenge (sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin. Cancer Res. 17, 3520-3526 (2011).
4. Hoos, A. et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin. Oncol. 37, 533-546 (2010).
5. Hoos, A., Britten, C. M., Huber, C. & O'Donnell-Tormey, J. A methodological framework to enhance the clinical success of cancer immunotherapy. Nat. Biotech. 29, 867-870 (2011).
6. Poole, R. M. Pembrolizumab: first global approval. Drugs 74, 1973-1981 (2014).
7. Wang, C. et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol. Res. 2, 846-856 (2014).
8. Lee, S. & Margolin, K. Cytokines in cancer immunotherapy. Cancers 3, 3856-3893 (2011).
9. Melero, I. et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509-524 (2014).
10. Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269-281 (2012).
11. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264 (2012).
12. Muller, A. J. & Scherle, P. A. Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat. Rev. Cancer 6, 613-625 (2006).
13. Gill, S. Going viral: chimeric antigen receptor T cell therapy for hematological malignancies. Immunol. Rev. 263, 68-89 (2015).
14. Linette, G. P. et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122, 863-871 (2013).
15. Marabelle, A. et al. Depleting tumor-specific T regs at a single site eradicates disseminated tumors. J. Clin. Invest. 123, 2447-2463 (2013).
16. Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135-146 (2014).
17. Srinivasan, R., Houghton, A. N. & Wolchok, J. D. Induction of autoantibodies against tyrosinase-related proteins following DNA vaccination: unexpected reactivity to a protein paralogue. Cancer Immun. 2, 8 (2002).
18. Printz, C. Spontaneous regression of melanoma may offer insight into cancer immunology. J. Natl Cancer Inst. 93, 1047-1048 (2001).
19. Waldhauer, I. & Steinle, A. NK cells and cancer immunosurveillance. Oncogene 27, 5932-5943 (2008).
20. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883-899 (2010).
21. Sica, A. & Bronte, V. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Invest. 117, 1155-1166 (2007).
22. Lewis, C. & Murdoch, C. Macrophage responses to hypoxia: implications for tumor progression and anticancer therapies. Am. J. Pathol. 167, 627-635 (2005).
23. Almand, B. et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J. Immunol. 166, 678-689 (2001).
24. + regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int. J. Cancer 126, 2635-2643 (2010).
25. Diaz-Montero, C. M. et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58, 49-59 (2009).
26. Whiteside, T. L. Induced regulatory T cells in inhibitory microenvironments created by cancer. Expert Opin. Biol. Ther. 14, 1411-1425 (2014).
27. Adeegbe, D. O. & Nishikawa, H. Natural and induced T regulatory cells in cancer. Front. Immunol. 4, 190 (2013).
28. Madar, S. Goldstein, I. & Rotter, V. 'Cancer associated fibroblasts' - more than meets the eye. Trends Mol. Med. 19, 447-453 (2013).
29. Galluzzi, L, Senovilla, L, Zitvogel, L. & Kroemer, G. The secret ally: immunostimulation by anticancer drugs. Nat. Rev. Drug Discov. 11, 215-233 (2012).
30. Kroemer, G., Galluzzi, L, Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51-72 (2013).
31. Sullivan, R. J., LoRusso, P. M. & Flaherty, K. T. The intersection of immune-directed and molecularly targeted therapy in advanced melanoma: where we have been, are, and will be. Clin. Cancer Res. 19, 5283-5291 (2013).
32. Lynch, T. J. et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter Phase II study J. Clin. Oncol. 30, 2046-2054 (2012).
33. Ribas, A., Hodi, F. S., Callahan, M., Konto, C. & Wolchok, J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368, 1365-1366 (2013).
34. Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237-251 (2012).
35. Liu, X. et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115, 3520-3530 (2010).
36. Friberg, M. et al. Indoleamine 2, 3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int. J. Cancer 101, 151-155 (2002).
37. Mautino, M. R., et al. Synergistic antitumor effects of combinatorial immune checkpoint inhibition with anti-PD- 1/PD-L antibodies and the IDO pathway inhibitors NLG-919 and indoximod in the context of active immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR. Cancer Res. 74 (Suppl. 19), 5023 (2014).
38. Pilotte, L. et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2, 3-dioxygenase. Proc. Natl Acad. Sci. USA 109, 2497-2502 (2012).
39. Van Zandt, M. C. et al. Discovery of (R)-2-amino-6-borono-2-(2-(piperidin- 1-yl)ethyl) hexanoic acid and congeners as highly potent inhibitors of human arginases I and II for treatment of myocardial reperfusion injury. J. Med. Chem. 56, 2568-2580 (2013).
40. Hagos, G. K. et al. Anti-inflammatory, antiproliferative, and cytoprotective activity of NO chimera nitrates of use in cancer chemoprevention. Mol. Pharmacol. 74, 1381-1391 (2008).
41. Molon, B. et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J. Exp. Med. 208, 1949-1962 (2011).
42. Serafini, P. et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J. Exp. Med. 203, 2691-2702 (2006).
43. Ghiringhelli, F et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1 β-dependent adaptive immunity against tumors. Nat. Med. 15, 1170-1178 (2009).
44. Adinolfi, E. et al. Expression of P2X7 receptor increases in vivo tumor growth. Cancer Res. 72, 2957-2969 (2012).
45. Meis, S. et al. NF546 [4, 4'-(carbonylbis(imino-3, 1-phenylene-carbonylimino-3, 1-(4- methyl-phenylene)-carbonylimino))-bis(1, 3-xylene-alpha, alpha'-diphosphonic acid) tetrasodium salt] is a non-nucleotide P2Y11 agonist and stimulates release of interleukin-8 from human monocyte-derived dendritic cells. J. Pharmacol. Exp. Ther. 332, 238-247 (2010).
46. + tumors. Proc. Natl Acad. Sci. USA 110, 14711-14716 (2013).
47. Chen, J. F, Eltzschig, H. K. & Fredholm, B. B. Adenosine receptors as drug targets - what are the challenges? Nat. Rev. Drug Discov. 12, 265-286 (2013).
48. Iannone, R., Miele, L., Maiolino, P., Pinto, A. & Morello, S. Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia 15, 1400-1409 (2013).
49. Bastid, J. et al. ENTPD1/CD39 is a promising therapeutic target in oncology. Oncogene 32, 1743-1751 (2013).
50. Wang, L. et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J. Clin. Invest. 121, 2371-2382 (2011).
51. Wang, D. & DuBois, R. N. The role of anti-inflammatory drugs in colorectal cancer. Ann. Rev. Med. 64, 131-144 (2013).
52. Af Forselles, K. J. et al. In vitro and in vivo characterization of PF-04418948, a novel, potent and selective prostaglandin EP 2 receptor antagonist. Br. J. Pharmacol. 164, 1847-1856 (2011).
53. Ma, X. et al. A prostaglandin E (PGE) receptor EP4 antagonist protects natural killer cells from PGE2-mediated immunosuppression and inhibits breast cancer metastasis. Oncoimmunology 2, e22647 (2013).
54. Highfill, S. L. et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci. Transl. Med. 6, 237ra67 (2014).
55. Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212-20217 (2013).
56. Sanford, D. E. et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin. Cancer Res. 19, 3404-3415 (2013).
57. Weitzenfeld, P. & Ben-Baruch, A. The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett. 352, 36-53 (2014).
58. Onier, N. et al. Cure of colon cancer metastasis in rats with the new lipid A OM 174. Apoptosis of tumor cells and immunization of rats. Clin. Exp. Metastasis 17, 299-306 (1999).
59. Geisse, J. et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J. Am. Acad. Dermatol. 50, 722-733 (2004).
60. Dudek, A. Z. et al. First in human phase I trial of 852A, a novel systemic Toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Clin. Cancer Res. 13, 7119-7125 (2007).
61. Northfelt, D. W. et al. A phase I dose-finding study of the novel toll-like receptor 8 agonist VTX-2337 in adult subjects with advanced solid tumors or lymphoma. Clin. Cancer Res. 20, 3683-3691 (2014).
62. Hwang, J. J. et al. A phase I study of HYB2055 in patients (pts) with advanced solid malignancies. J. Clin. Oncol. 22 (Suppl.), 3111 (2004).
63. Yoon, J. H. et al. Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes. EMBO Mol. Med. 5, 1720-1739 (2013).
64. Khalili, J. S. et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin. Cancer Res. 18, 5329-5340 (2012).
65. Schilling, B. et al. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int. J. Cancer 133, 1653-1663 (2013).
66. Eyob, H., Ekiz, H. A. & Welm, A. L. RON promotes the metastatic spread of breast carcinomas by subverting antitumor immune responses. Oncoimmunology 2, e25670 (2013).
67. Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264-1272 (2013).
68. Ali, K. et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510, 407-411 (2014).
69. Schmid, Michael, C. et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3Kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715-727 (2011).
70. Sikalidis, A. Amino acids and immune response: a role for cysteine, glutamine, phenylalanine, tryptophan and arginine in T-cell function and cancer? Pathol. Oncol. Res. 21, 9-17 (2015).
71. Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762-774 (2004).
72. Okamoto, A. et al. Indoleamine 2, 3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin. Cancer Res. 11, 6030-6039 (2005).
73. Belladonna, M. L., Orabona, C., Grohmann, U. & Puccetti, P. TGF-β and kynurenines as the key to infectious tolerance. Trends Mol. Med. 15, 41-49 (2009).
74. Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203 (2011).
75. Yue, E. W. 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, 7364-7367 (2009).
76. Fallarino, F. et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 176, 6752-6761 (2006).
77. Rodriguez, P. C. et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 64, 5839-5849 (2004).
78. Rodriguez, P. C. et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 69, 1553-1560 (2009).
79. de Boniface, J., Mao, Y., Schmidt-Mende, J., Kiessling, R. & Poschke, I. Expression patterns of the immunomodulatory enzyme arginase 1 in blood, lymph nodes and tumor tissue of early-stage breast cancer patients. Oncoimmunology 1, 1305-1312 (2012).
80. Serafini, P. Myeloid derived suppressor cells in physiological and pathological conditions: the good, the bad, and the ugly. Immunol. Res. 57, 172-184 (2013).
81. De Santo, C. et al. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc. Natl Acad. Sci. USA 102, 4185-4190 (2005).
82. + T cells. J. Clin. Invest. 116, 2777-2790 (2006).
83. Califano, J. A. et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 21, 30-38 (2015).
84. Weed, D. T. et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 21, 39-48 (2015).
85. Sitkovsky, M. & Ohta, A. Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer. J. Mol. Med. 91, 147-155 (2013).
86. Blay, J., White, T. D. & Hoskin, D. W. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 57, 2602-2605 (1997).
87. Yang, M. et al. HIF-dependent induction of adenosine receptor A2b skews human dendritic cells to a Th2-stimulating phenotype under hypoxia. Immunol. Cell Biol. 88, 165-171 (2010).
88. Sitkovsky, M. V. T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol. 30, 102-108 (2009).
89. Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257-1265 (2007).
90. + regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front. Immunol. 3, 190 (2012).
91. + regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 139, 1030-1040 (2010).
92. Chalmin, F. et al. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity 36, 362-373 (2012).
93. + regulatory T cells to extracellular metabolites nicotinamide adenine dinucleotide and ATP: a role for P2X7 receptors. J. Immunol. 175, 3075-3083 (2005).
94. Schenk, U. et al. ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci. Signal. 4, ra12 (2011).
95. Bian, S. et al. P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PLoS ONE 8, e60184 (2013).
96. Di Virgilio, F., Ferrari, D. & Adinolfi, E. P2X7: a growth-promoting receptor - implications for cancer. Purinergic Signal. 5, 251-256 (2009).
97. Bianchi, G. et al. ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment. Cell Death Dis. 5, e1135 (2014).
98. North, R. A. & Jarvis, M. F. P2X receptors as drug targets. Mol. Pharmacol. 83, 759-769 (2013).
99. Csóka, B. et al. Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J. 26, 376-386 (2012).
100. + cells. J. Immunol. 187, 6120-6129 (2011).
101. Cekic, C. et al. Adenosine A 2B receptor blockade slows growth of bladder and breast tumors. J. Immunol. 188, 198-205 (2012).
102. Kalla, R. V. & Zablocki, J. Progress in the discovery of selective, high affinity A2B adenosine receptor antagonists as clinical candidates. Purinergic Signal. 5, 21-29 (2009).
103. + Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225-1232 (2007).
104. Jie, H. B. et al. Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients. Br. J. Cancer 109, 2629-2635 (2013).
105. Serra, S. et al. CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood 118, 6141-6152 (2011).
106. +-infiltrating T cells contribute to adenosine-mediated T cell hyporesponsiveness. J. Immunol. 183, 6157-6166 (2009).
107. Michaud, M. et al. Subversion of the chemotherapy-induced anticancer immune response by the ecto-ATPase CD39. Oncoimmunology 1, 393-395 (2012).
108. Al-Rashida, M. & Iqbal, J. Therapeutic potentials of ecto-nucleoside triphosphate diphosphohydrolase, ecto-nucleotide pyrophosphatase/phosphodiesterase, ecto-5′-nucleotidase, and alkaline phosphatase inhibitors. Med. Res. Rev. 34, 703-743 (2014).
109. Lévesque, S. A., Lavoie, É. G., Lecka, J., Bigonnesse, F. & Sévigny, J. Specificity of the ecto-ATPase inhibitor ARL 67156 on human and mouse ectonucleotidases. Br. J. Pharmacol. 152, 141-150 (2007).
110. Lecka, J. et al. 8-BuS-ATP derivatives as specific NTPDase1 inhibitors. Br. J. Pharmacol. 169, 179-196 (2013).
111. Synnestvedt, K. et al. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Invest. 110, 993-1002 (2002).
112. Stagg, J. & Smyth, M. J. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29, 5346-5358 (2010).
113. Mandapathil, M. et al. Adenosine and prostaglandin e2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J. Biol. Chem. 285, 27571-27580 (2010).
114. Clayton, A., Al-Taei, S., Webber, J., Mason, M. D. & Tabi, Z. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J. Immunol. 187, 676-683 (2011).
115. + cells. Clin. Exp. Immunol. 177, 531-543 (2014).
116. Stagg, J. et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc. Natl Acad. Sci. USA 107, 1547-1552 (2010).
117. Xu, S. et al. Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas. Neuro. Oncol. 15, 1160-1172 (2013).
118. Forte, G. et al. Inhibition of CD73 improves B cellmediated anti-tumor immunity in a mouse model of melanoma. J. Immunol. 189, 2226-2233 (2012).
119. Knapp, K. et al. Crystal structure of the human ecto-5′-nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure 20, 2161-2173 (2012).
120. Ogino, S. et al. Cyclooxygenase-2 expression Is an independent predictor of poor prognosis in colon cancer. Clin. Cancer Res. 14, 8221-8227 (2008).
121. Kaidi, A., Qualtrough, D., Williams, A. C. & Paraskeva, C. Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res. 66, 6683-6691 (2006).
122. Min/+ mouse polyps. Carcinogenesis 32, 1333-1339 (2011).
123. + adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism. J. Immunol. 177, 246-254 (2006).
124. Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R. P. & Kalinski, P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 118, 5498-5505 (2011).
125. Duan, B. et al. Distinct roles of adenylyl cyclase VII in regulating the immune responses in mice. J. Immunol. 185, 335-344 (2010).
126. Mao, Y. et al. Inhibition of tumor-derived prostaglandin-E2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin. Cancer Res. 20, 4096-4106 (2014).
127. Holt, D., Ma, X., Kundu, N. & Fulton, A. Prostaglandin E2 (PGE2) suppresses natural killer cell function primarily through the PGE2 receptor EP4. Cancer Immunol. Immunother. 60, 1577-1586 (2011).
128. Antonova, M. et al. The pharmacological effect of BGC20-1531, a novel prostanoid EP 4 receptor antagonist, in the prostaglandin E 2 human model of headache. J. Headache Pain 12, 551-559 (2011).
129. Jiang, L. I., Collins, J., Davis, R., Fraser, I. D. & Sternweis, P. C. Regulation of cAMP responses by the G12-13 pathway converges on adenylyl cyclase VII. J. Biol. Chem. 283, 23429-23439 (2008).
130. Whiteside, T. L. & Jackson, E. K. Adenosine and prostaglandin E2 production by human inducible regulatory T cells in health and disease. Front. Immunol. 4, 212 (2013).
131. Mancini, R. J., Stutts, L., Ryu, K. A., Tom, J. K. & Esser-Kahn, A. P. Directing the immune system with chemical compounds. ACS Chem. Biol. 9, 1075-1085 (2014).
132. Pradere, J. P., Dapito, D. H. & Schwabe, R. F. The yin and yang of Toll-like receptors in cancer. Oncogene 33, 3485-3495 (2014).
133. Guiducci, C., Vicari, A. P., Sangaletti, S., Trinchieri, G. & Colombo, M. P. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 65, 3437-3446 (2005).