Recent Advances of Small Molecular Regulators Targeting G Protein- Coupled Receptors Family for Oncology Immunotherapy

Peng       He; Wenbo       Zhou; Mingyao       Liu; Yihua       Chen
doi:10.2174/1568026619666190628115644
Abstract

The great clinical success of chimeric antigen receptor T cell (CAR-T) and PD-1/PDL-1 inhibitor therapies suggests the drawing of a cancer immunotherapy age. However, a considerable proportion of cancer patients currently receive little benefit from these treatment modalities, indicating that multiple immunosuppressive mechanisms exist in the tumor microenvironment. In this review, we mainly discuss recent advances in small molecular regulators targeting G Protein-Coupled Receptors (GPCRs) that are associated with oncology immunomodulation, including chemokine receptors, purinergic receptors, prostaglandin E receptor EP4 and opioid receptors. Moreover, we outline how they affect tumor immunity and neoplasia by regulating immune cell recruitment and modulating tumor stromal cell biology. We also summarize the data from recent clinical advances in small molecular regulators targeting these GPCRs, in combination with immune checkpoints blockers, such as PD-1/PDL-1 and CTLA4 inhibitors, for cancer treatments.
Keywords: G protein-coupled receptors (GPCRs), Immunotherapy, Small molecular regulator, Combination immunotherapy, FDA, TAMs.
« Previous
Graphical Abstract

[1] 
Liu, Y.; An, S.; Ward, R.; Yang, Y.; Guo, X.X.; Li, W.; Xu, T.R. G protein-coupled receptors as promising cancer targets. Cancer Lett.,  2016, 376(2), 226-239.
[http://dx.doi.org/10.1016/j.canlet.2016.03.031] [PMID:  27000991] 
[2] 
Sunshine, J.; Taube, J.M. PD-1/PD-L1 inhibitors. Curr. Opin. Pharmacol.,  2015, 23, 32-38.
[http://dx.doi.org/10.1016/j.coph.2015.05.011] [PMID:  26047524] 
[3] 
Raedler, L.A.  Opdivo (Nivolumab): Second PD-1 inhibitor receives FDA approval for unresectable or metastatic melanoma.  Am. Health Drug Benefits,,  2015,  8 (Spec Feature). , 180-183.
[PMID: 26629287 ] 
[4] 
Porter, D.L.; Hwang, W-T.; Frey, N.V.; Lacey, S.F.; Shaw, P.A.; Loren, A.W.; Bagg, A.; Marcucci, K.T.; Shen, A.; Gonzalez, V.; Ambrose, D.; Grupp, S.A.; Chew, A.; Zheng, Z.; Milone, M.C.; Levine, B.L.; Melenhorst, J.J.; June, C.H. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med.,  2015, 7(303), 303.
[http://dx.doi.org/10.1126/scitranslmed.aac5415] 
[5] 
Schumacher, T.N.; Schreiber, R.D. Neoantigens in cancer immunotherapy. Science,  2015, 348(6230), 69-74.
[http://dx.doi.org/10.1126/science.aaa4971] [PMID:  25838375] 
[6] 
National Medical Products Administration. PD-1 antibody drug approved for marketing. (Available at:
                    http://www.nmpa.gov.cn/WS04/CL2056/228364.html. 
[7] 
Fukumura, D.; Kloepper, J.; Amoozgar, Z.; Duda, D.G.; Jain, R.K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol.,  2018, 15(5), 325-340.
[http://dx.doi.org/10.1038/nrclinonc.2018.29] [PMID:  29508855] 
[8] 
Immune checkpoint inhibitors In: Reactions Weekly; Springer Nature, Switzerland,  2018, Vol. 1717,  pp. 159-159.
[http://dx.doi.org/10.1007/s40278-018-51229-3] 
[9] 
Yang, Y. Cancer immunotherapy: Harnessing the immune system to battle cancer. J. Clin. Invest.,  2015, 125(9), 3335-3337.
[http://dx.doi.org/10.1172/JCI83871] [PMID:  26325031] 
[10] 
Shalapour, S.; Karin, M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J. Clin. Invest.,  2015, 125(9), 3347-3355.
[http://dx.doi.org/10.1172/JCI80007] [PMID:  26325032] 
[11] 
Schreiber, R.D.; Old, L.J.; Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science,  2011, 331(6024), 1565-1570.
[http://dx.doi.org/10.1126/science.1203486] [PMID:  21436444] 
[12] 
Fredriksson, R.; Lagerström, M.C.; Lundin, L-G.; Schiöth, H.B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol.,  2003, 63(6), 1256-1272.
[http://dx.doi.org/10.1124/mol.63.6.1256] [PMID:  12761335] 
[13] 
Lagerström, M.C.; Schiöth, H.B. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat. Rev. Drug Discov.,  2008, 7(4), 339-357.
[http://dx.doi.org/10.1038/nrd2518] [PMID:  18382464] 
[14] 
Dorsam, R.T.; Gutkind, J.S. G-protein-coupled receptors and cancer. Nat. Rev. Cancer,  2007, 7(2), 79-94.
[http://dx.doi.org/10.1038/nrc2069] [PMID:  17251915] 
[15] 
Seifert, R.; Wenzel-Seifert, K. Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch. Pharmacol.,  2002, 366(5), 381-416.
[http://dx.doi.org/10.1007/s00210-002-0588-0] [PMID:  12382069] 
[16] 
Salon, J.A.; Lodowski, D.T.; Palczewski, K. The significance of G protein-coupled receptor crystallography for drug discovery. Pharmacol. Rev.,  2011, 63(4), 901-937.
[http://dx.doi.org/10.1124/pr.110.003350] [PMID:  21969326] 
[17] 
Shurin, M.R. Dual role of immunomodulation by anticancer chemotherapy. Nat. Med.,  2013, 19(1), 20-22.
[http://dx.doi.org/10.1038/nm.3045] [PMID:  23296003] 
[18] 
Rot, A.; von Andrian, U.H. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu. Rev. Immunol.,  2004, 22(1), 891-928.
[http://dx.doi.org/10.1146/annurev.immunol.22.012703.104543] [PMID:  15032599] 
[19] 
Murphy, P.M.; Baggiolini, M.; Charo, I.F.; Hébert, C.A.; Horuk, R.; Matsushima, K.; Miller, L.H.; Oppenheim, J.J.; Power, C.A. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev.,  2000, 52(1), 145-176.
[PMID:  10699158] 
[20] 
Gerard, C.; Rollins, B.J. Chemokines and disease. Nat. Immunol.,  2001, 2(2), 108-115.
[http://dx.doi.org/10.1038/84209] [PMID:  11175802] 
[21] 
Whiteside, T.L. Targeting adenosine in cancer immunotherapy: a review of recent progress. Expert Rev. Anticancer Ther.,  2017, 17(6), 527-535.
[http://dx.doi.org/10.1080/14737140.2017.1316197] [PMID:  28399672] 
[22] 
Garcia, J.B.S.; Cardoso, M.G.M.; Dos-Santos, M.C. Opioids and the immune system: clinical relevance. Rev. Bras. Anestesiol.,  2012, 62(5), 709-718.
[http://dx.doi.org/10.1016/S0034-7094(12)70169-1] [PMID:  22999403] 
[23] 
Dale, H.H.; Laidlaw, P.P. The physiological action of β-iminazolylethylamine. J. Physiol.,  1910, 41(5), 318-344.
[http://dx.doi.org/10.1113/jphysiol.1910.sp001406] [PMID:  16993030] 
[24] 
Schaller, T.H.; Batich, K.A.; Suryadevara, C.M.; Desai, R.; Sampson, J.H. Chemokines as adjuvants for immunotherapy: implications for immune activation with CCL3. Expert Rev. Clin. Immunol.,  2017, 13(11), 1049-1060.
[http://dx.doi.org/10.1080/1744666X.2017.1384313] [PMID:  28965431] 
[25] 
Bobanga, I.D.; Petrosiute, A.; Huang, A.Y. Chemokines as cancer vaccine adjuvants. Vaccines (Basel),  2013, 1(4), 444-462.
[http://dx.doi.org/10.3390/vaccines1040444] [PMID:  24967094] 
[26] 
Bachelerie, F.; Ben-Baruch, A.; Burkhardt, A.M.; Combadiere, C.; Farber, J.M.; Graham, G.J.; Horuk, R.; Sparre-Ulrich, A.H.; Locati, M.; Luster, A.D.; Mantovani, A.; Matsushima, K.; Murphy, P.M.; Nibbs, R.; Nomiyama, H.; Power, C.A.; Proudfoot, A.E.; Rosenkilde, M.M.; Rot, A.; Sozzani, S.; Thelen, M.; Yoshie, O.; Zlotnik, A. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol. Rev.,  2013, 66(1), 1-79.
[http://dx.doi.org/10.1124/pr.113.007724] [PMID:  24218476] 
[27] 
Taddese, B.; Deniaud, M.; Garnier, A.; Tiss, A.; Guissouma, H.; Abdi, H.; Henrion, D.; Chabbert, M. Evolution of chemokine receptors is driven by mutations in the sodium binding site. PLOS Comput. Biol.,  2018, 14(6)e1006209
[http://dx.doi.org/10.1371/journal.pcbi.1006209] [PMID:  29912865] 
[28] 
Nagarsheth, N.; Wicha, M.S.; Zou, W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol.,  2017, 17(9), 559-572.
[http://dx.doi.org/10.1038/nri.2017.49] [PMID:  28555670] 
[29] 
Zou, W.; Wolchok, J.D.; Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med.,  2016, 8(328), 328-324.
[http://dx.doi.org/doi: 10.1126/scitranslmed.aad7118.] [PMID:  26936508] 
[30] 
Kryczek, I.; Banerjee, M.; Cheng, P.; Vatan, L.; Szeliga, W.; Wei, S.; Huang, E.; Finlayson, E.; Simeone, D.; Welling, T.H.; Chang, A.; Coukos, G.; Liu, R.; Zou, W. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood,  2009, 114(6), 1141-1149.
[http://dx.doi.org/10.1182/blood-2009-03-208249] [PMID:  19470694] 
[31] 
Kryczek, I.; Zhao, E.; Liu, Y.; Wang, Y.; Vatan, L.; Szeliga, W.; Moyer, J.; Klimczak, A.; Lange, A.; Zou, W. Human TH17 cells are long-lived effector memory cells. Sci. Transl. Med.,  2011, 3(104), 100-104.
[http://dx.doi.org/10.1126/scitranslmed.3002949] 
[32] 
Kvistborg, P.; Shu, C.J.; Heemskerk, B.; Fankhauser, M.; Thrue, C.A.; Toebes, M.; van Rooij, N.; Linnemann, C.; van Buuren, M.M.; Urbanus, J.H.; Beltman, J.B.; Thor Straten, P.; Li, Y.F.; Robbins, P.F.; Besser, M.J.; Schachter, J.; Kenter, G.G.; Dudley, M.E.; Rosenberg, S.A.; Haanen, J.B.; Hadrup, S.R.; Schumacher, T.N. TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients. OncoImmunology,  2012, 1(4), 409-418.
[http://dx.doi.org/10.4161/onci.18851] [PMID:  22754759] 
[33] 
Banchereau, J.; Palucka, A.K. Dendritic cells as therapeutic vaccines against cancer. Nat. Rev. Immunol.,  2005, 5(4), 296-306.
[http://dx.doi.org/10.1038/nri1592] [PMID:  15803149] 
[34] 
Aspord, C.; Pedroza-Gonzalez, A.; Gallegos, M.; Tindle, S.; Burton, E.C.; Su, D.; Marches, F.; Banchereau, J.; Palucka, A.K. Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. J. Exp. Med.,  2007, 204(5), 1037-1047.
[http://dx.doi.org/10.1084/jem.20061120] [PMID:  17438063] 
[35] 
Zou, W.; Machelon, V.; Coulomb-L’Hermin, A.; Borvak, J.; Nome, F.; Isaeva, T.; Wei, S.; Krzysiek, R.; Durand-Gasselin, I.; Gordon, A.; Pustilnik, T.; Curiel, D.T.; Galanaud, P.; Capron, F.;  F, Gordon.; A, Pustilnik.; T, Curiel. D; T, Galanaud. ; P, Capron.; Emilie, D.; Curiel, T.J. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med.,  2001, 7(12), 1339-1346.
[http://dx.doi.org/10.1038/nm1201-1339] [PMID:  11726975] 
[36] 
Kryczek, I.; Lange, A.; Mottram, P.; Alvarez, X.; Cheng, P.; Hogan, M.; Moons, L.; Wei, S.; Zou, L.; Machelon, V.; Emilie, D.; Terrassa, M.; Lackner, A.; Curiel, T.J.; Carmeliet, P.; Zou, W. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res.,  2005, 65(2), 465-472.
[PMID:  15695388] 
[37] 
Qian, B-Z.; Li, J.; Zhang, H.; Kitamura, T.; Zhang, J.; Campion, L.R.; Kaiser, E.A.; Snyder, L.A.; Pollard, J.W. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature,  2011, 475(7355), 222-225.
[http://dx.doi.org/10.1038/nature10138] [PMID:  21654748] 
[38] 
Pollard, J.W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer,  2004, 4(1), 71-78.
[http://dx.doi.org/10.1038/nrc1256] [PMID:  14708027] 
[39] 
Pollard, J.W. Trophic macrophages in development and disease. Nat. Rev. Immunol.,  2009, 9(4), 259-270.
[http://dx.doi.org/10.1038/nri2528] [PMID:  19282852] 
[40] 
Waugh, D.J.J.; Wilson, C. The interleukin-8 pathway in cancer. Clin. Cancer Res.,  2008, 14(21), 6735-6741.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-4843] [PMID:  18980965] 
[41] 
Lechner, M.G.; Russell, S.M.; Bass, R.S.; Epstein, A.L. Chemokines, costimulatory molecules and fusion proteins for the immunotherapy of solid tumors. Immunotherapy,  2011, 3(11), 1317-1340.
[http://dx.doi.org/10.2217/imt.11.115] [PMID:  22053884] 
[42] 
Liang, M.; Mallari, C.; Rosser, M.; Ng, H.P.; May, K.; Monahan, S.; Bauman, J.G.; Islam, I.; Ghannam, A.; Buckman, B.; Shaw, K.; Wei, G.P.; Xu, W.; Zhao, Z.; Ho, E.; Shen, J.; Oanh, H.; Subramanyam, B.; Vergona, R.; Taub, D.; Dunning, L.; Harvey, S.; Snider, R.M.; Hesselgesser, J.; Morrissey, M.M.; Perez, H.D. Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J. Biol. Chem.,  2000, 275(25), 19000-19008.
[http://dx.doi.org/10.1074/jbc.M001222200] [PMID:  10748002] 
[43] 
Vergunst, C.E.; Gerlag, D.M.; von Moltke, L.; Karol, M.; Wyant, T.; Chi, X.; Matzkin, E.; Leach, T.; Tak, P.P. MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study. Arthritis Rheum.,  2009, 60(12), 3572-3581.
[http://dx.doi.org/10.1002/art.24978] [PMID:  19950299] 
[44] 
Gladue, R.P.; Cole, S.H.; Roach, M.L.; Tylaska, L.A.; Nelson, R.T.; Shepard, R.M.; McNeish, J.D.; Ogborne, K.T.; Neote, K.S. The human specific CCR1 antagonist CP-481,715 inhibits cell infiltration and inflammatory responses in human CCR1 transgenic mice. J. Immunol.,  2006, 176(5), 3141-3148.
[http://dx.doi.org/10.4049/jimmunol.176.5.3141] [PMID:  16493073] 
[45] 
Kerstjens, H.A.; Bjermer, L.; Eriksson, L.; Dahlström, K.; Vestbo, J. Tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patients. Respir. Med.,  2010, 104(9), 1297-1303.
[http://dx.doi.org/10.1016/j.rmed.2010.04.010] [PMID:  20466530] 
[46] 
Yamasaki, R.; Liu, L.; Lin, J.; Ransohoff, R.M. Role of CCR2 in immunobiology and neurobiology. Clin. Exp. Neuroimmunol.,  2012, 3(1), 16-29.
[http://dx.doi.org/10.1111/j.1759-1961.2011.00024.x] 
[47] 
Penton-Rol, G.; Polentarutti, N.; Luini, W.; Borsatti, A.; Mancinelli, R.; Sica, A.; Sozzani, S.; Mantovani, A. Selective inhibition of expression of the chemokine receptor CCR2 in human monocytes by IFN-γ. J. Immunol.,  1998, 160(8), 3869-3873.
[PMID:  9558092] 
[48] 
Steidl, C.; Lee, T.; Shah, S.P.; Farinha, P.; Han, G.; Nayar, T.; Delaney, A.; Jones, S.J.; Iqbal, J.; Weisenburger, D.D.; Bast, M.A.; Rosenwald, A.; Muller-Hermelink, H.K.; Rimsza, L.M.; Campo, E.; Delabie, J.; Braziel, R.M.; Cook, J.R.; Tubbs, R.R.; Jaffe, E.S.; Lenz, G.; Connors, J.M.; Staudt, L.M.; Chan, W.C.; Gascoyne, R.D. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N. Engl. J. Med.,  2010, 362(10), 875-885.
[http://dx.doi.org/10.1056/NEJMoa0905680] [PMID:  20220182] 
[49] 
Horuk, R. Chemokine receptor antagonists: overcoming developmental hurdles. Nat. Rev. Drug Discov.,  2009, 8(1), 23-33.
[http://dx.doi.org/10.1038/nrd2734] [PMID:  19079127] 
[50] 
Xue, C-B.; Feng, H.; Cao, G.; Huang, T.; Glenn, J.; Anand, R.; Meloni, D.; Zhang, K.; Kong, L.; Wang, A.; Zhang, Y.; Zheng, C.; Xia, M.; Chen, L.; Tanaka, H.; Han, Q.; Robinson, D.J.; Modi, D.; Storace, L.; Shao, L.; Sharief, V.; Li, M.; Galya, L.G.; Covington, M.; Scherle, P.; Diamond, S.; Emm, T.; Yeleswaram, S.; Contel, N.; Vaddi, K.; Newton, R.; Hollis, G.; Friedman, S.; Metcalf, B. Discovery of INCB3284, a potent, selective, and orally bioavailable hCCR2 antagonist. ACS Med. Chem. Lett.,  2011, 2(6), 450-454.
[http://dx.doi.org/10.1021/ml200030q] [PMID:  24900329] 
[51] 
Hughes, R.O.; Rogier, D.J.; Devraj, R.; Zheng, C.; Cao, G.; Feng, H.; Xia, M.; Anand, R.; Xing, L.; Glenn, J.; Zhang, K.; Covington, M.; Morton, P.A.; Hutzler, J.M.; Davis, J.W., II; Scherle, P.; Baribaud, F.; Bahinski, A.; Mo, Z.L.; Newton, R.; Metcalf, B.; Xue, C.B. Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile. Bioorg. Med. Chem. Lett.,  2011, 21(9), 2626-2630.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.034] [PMID:  21315584] 
[52] 
Lagu, B.; Gerchak, C.; Pan, M.; Hou, C.; Singer, M.; Malaviya, R.; Matheis, M.; Olini, G.; Cavender, D.; Wachter, M. Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma. Bioorg. Med. Chem. Lett.,  2007, 17(15), 4382-4386.
[http://dx.doi.org/10.1016/j.bmcl.2007.01.115] [PMID:  17587570] 
[53] 
Curiel, T.J.; Coukos, G.; Zou, L.; Alvarez, X.; Cheng, P.; Mottram, P.; Evdemon-Hogan, M.; Conejo-Garcia, J.R.; Zhang, L.; Burow, M.; Zhu, Y.; Wei, S.; Kryczek, I.; Daniel, B.; Gordon, A.; Myers, L.; Lackner, A.; Disis, M.L.; Knutson, K.L.; Chen, L.; Zou, W. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med.,  2004, 10(9), 942-949.
[http://dx.doi.org/10.1038/nm1093] [PMID:  15322536] 
[54] 
Pere, H.; Montier, Y.; Bayry, J.; Quintin-Colonna, F.; Merillon, N.; Dransart, E.; Badoual, C.; Gey, A.; Ravel, P.; Marcheteau, E.; Batteux, F.; Sandoval, F.; Adotevi, O.; Chiu, C.; Garcia, S.; Tanchot, C.; Lone, Y.C.; Ferreira, L.C.; Nelson, B.H.; Hanahan, D.; Fridman, W.H.; Johannes, L.; Tartour, E.A. CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens. Blood,  2011, 118(18), 4853-4862.
[http://dx.doi.org/10.1182/blood-2011-01-329656] [PMID:  21908423] 
[55] 
Pease, J.E.; Horuk, R. Chemokine receptor antagonists: Part 1. Expert Opin. Ther. Pat.,  2009, 19(1), 39-58.
[http://dx.doi.org/10.1517/13543770802641346] [PMID:  19441897] 
[56] 
Liu, T.; Weng, Z.; Dong, X.; Hu, Y. Recent advances in the development of small-molecule CCR5 inhibitors for HIV. Mini Rev. Med. Chem.,  2010, 10(13), 1277-1292.
[http://dx.doi.org/10.2174/13895575110091277] [PMID:  20854256] 
[57] 
Palani, A.; Shapiro, S.; Clader, J.W.; Greenlee, W.J.; Cox, K.; Strizki, J.; Endres, M.; Baroudy, B.M. Discovery of 4-[(Z)-(4-Bromophenyl)- (ethoxyimino)methyl]-1‘-[(2,4-dimethyl-3-pyridi-nyl) carbonyl]-4‘-methyl-1,4‘-bipiperidine N-Oxide (SCH 3511-25): an orally bioavailable human CCR5 antagonist for the Treatment of HIV Infection. J. Med. Chem.,  2001, 44(21), 3339-3342.
[http://dx.doi.org/10.1021/jm015526o] [PMID:  11585437] 
[58] 
Xue, C-B.; Chen, L.; Cao, G.; Zhang, K.; Wang, A.; Meloni, D.; Glenn, J.; Anand, R.; Xia, M.; Kong, L.; Huang, T.; Feng, H.; Zheng, C.; Li, M.; Galya, L.; Zhou, J.; Shin, N.; Baribaud, F.; Solomon, K.; Scherle, P.; Zhao, B.; Diamond, S.; Emm, T.; Keller, D.; Contel, N.; Yeleswaram, S.; Vaddi, K.; Hollis, G.; Newton, R.; Friedman, S.; Metcalf, B. Discovery of INCB9471, a potent, selective, and orally bioavailable CCR5 antagonist with potent anti-HIV-1 activity. ACS Med. Chem. Lett.,  2010, 1(9), 483-487.
[http://dx.doi.org/10.1021/ml1001536] [PMID:  24900235] 
[59] 
Maeda, K.; Nakata, H.; Koh, Y.; Miyakawa, T.; Ogata, H.; Takaoka, Y.; Shibayama, S.; Sagawa, K.; Fukushima, D.; Moravek, J.; Koyanagi, Y.; Mitsuya, H. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. J. Virol.,  2004, 78(16), 8654-8662.
[http://dx.doi.org/10.1128/JVI.78.16.8654-8662.2004] [PMID:  15280474] 
[60] 
Gerlag, D.M.; Hollis, S.; Layton, M.; Vencovský, J.; Szekanecz, Z.; Braddock, M.; Tak, P.P.; Group, E.S. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate. Arthritis Rheum.,  2010, 62(11), 3154-3160.
[http://dx.doi.org/10.1002/art.27652] [PMID:  20662070] 
[61] 
Baba, M.; Nishimura, O.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Iizawa, Y.; Shiraishi, M.; Aramaki, Y.; Okonogi, K.; Ogawa, Y.; Meguro, K.; Fujino, M. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA,  1999, 96(10), 5698-5703.
[http://dx.doi.org/10.1073/pnas.96.10.5698] [PMID:  10318947] 
[62] 
Baba, M.; Takashima, K.; Miyake, H.; Kanzaki, N.; Teshima, K.; Wang, X.; Shiraishi, M.; Iizawa, Y. TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans. Antimicrob. Agents Chemother.,  2005, 49(11), 4584-4591.
[http://dx.doi.org/10.1128/AAC.49.11.4584-4591.2005] [PMID:  16251299] 
[63] 
Guo, F.; Wang, Y.; Liu, J.; Mok, S.C.; Xue, F.; Zhang, W. CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene,  2016, 35(7), 816-826.
[http://dx.doi.org/10.1038/onc.2015.139] [PMID:  25961926] 
[64] 
Cascieri, M.A.; Springer, M.S. The chemokine/chemokine-receptor family: Potential and progress for therapeutic intervention. Curr. Opin. Chem. Biol.,  2000, 4(4), 420-427.
[http://dx.doi.org/10.1016/S1367-5931(00)00113-7] [PMID:  10959770] 
[65] 
Hernandez, P.A.; Gorlin, R.J.; Lukens, J.N.; Taniuchi, S.; Bohinjec, J.; Francois, F.; Klotman, M.E.; Diaz, G.A. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat. Genet.,  2003, 34(1), 70-74.
[http://dx.doi.org/10.1038/ng1149] [PMID:  12692554] 
[66] 
Wu, B.; Chien, E.Y.T.; Mol, C.D.; Fenalti, G.; Liu, W.; Katritch, V.; Abagyan, R.; Brooun, A.; Wells, P.; Bi, F.C.; Hamel, D.J.; Kuhn, P.; Handel, T.M.; Cherezov, V.; Stevens, R.C. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science,  2010, 330(6007), 1066-1071.
[http://dx.doi.org/10.1126/science.1194396] [PMID:  20929726] 
[67] 
Furusato, B.; Mohamed, A.; Uhlén, M.; Rhim, J.S. CXCR4 and cancer. Pathol. Int.,  2010, 60(7), 497-505.
[http://dx.doi.org/10.1111/j.1440-1827.2010.02548.x] [PMID:  20594270] 
[68] 
De Clercq, E. The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil). Biochem. Pharmacol.,  2009, 77(11), 1655-1664.
[http://dx.doi.org/10.1016/j.bcp.2008.12.014] [PMID:  19161986] 
[69] 
Thomlinson, R.H.; Gray, L.H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer,  1955, 9(4), 539-549.
[http://dx.doi.org/10.1038/bjc.1955.55] [PMID:  13304213] 
[70] 
Hatfield, S.M.; Kjaergaard, J.; Lukashev, D.; Schreiber, T.H.; Belikoff, B.; Abbott, R.; Sethumadhavan, S.; Philbrook, P.; Ko, K.; Cannici, R.; Thayer, M.; Rodig, S.; Kutok, J.L.; Jackson, E.K.; Karger, B.; Podack, E.R.; Ohta, A.; Sitkovsky, M.V. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl. Med.,  2015, 7(277), 230-277.
[http://dx.doi.org/10.1126/scitranslmed.aaa1260] 
[71] 
Semenza, G.L. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest.,  2013, 123(9), 3664-3671.
[http://dx.doi.org/10.1172/JCI67230] [PMID:  23999440] 
[72] 
Busse, M.; Vaupel, P. Accumulation of purine catabolites in solid tumors exposed to therapeutic hyperthermia. Experientia,  1996, 52(5), 469-473.
[http://dx.doi.org/10.1007/BF01919318] [PMID:  8641385] 
[73] 
Deaglio, S.; Dwyer, K.M.; Gao, W.; Friedman, D.; Usheva, A.; Erat, A.; Chen, J.F.; Enjyoji, K.; Linden, J.; Oukka, M.; Kuchroo, V.K.; Strom, T.B.; Robson, S.C. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med.,  2007, 204(6), 1257-1265.
[http://dx.doi.org/10.1084/jem.20062512] [PMID:  17502665] 
[74] 
Antonioli, L.; Colucci, R.; La Motta, C.; Tuccori, M.; Awwad, O.; Da Settimo, F.; Blandizzi, C.; Fornai, M. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr. Drug Targets,  2012, 13(6), 842-862.
[http://dx.doi.org/10.2174/138945012800564095] [PMID:  22250650] 
[75] 
Lotze, M.T.; Zeh, H.J.; Rubartelli, A.; Sparvero, L.J.; Amoscato, A.A.; Washburn, N.R.; Devera, M.E.; Liang, X.; Tör, M.; Billiar, T. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol. Rev.,  2007, 220(1), 60-81.
[http://dx.doi.org/10.1111/j.1600-065X.2007.00579.x] [PMID:  17979840] 
[76] 
Di Virgilio, F.; Adinolfi, E. Extracellular purines, purinergic receptors and tumor growth. Oncogene,  2017, 36(3), 293-303.
[http://dx.doi.org/10.1038/onc.2016.206] [PMID:  27321181] 
[77] 
Guzman, S.J.; Gerevich, Z. P2Y Receptors in synaptic transmission and plasticity: therapeutic potential in cognitive dysfunction. Neural Plast.,  2016, 20161207393
[http://dx.doi.org/10.1155/2016/1207393] [PMID:  27069691] 
[78] 
Gur, S.; Hellstrom, W.J.G. Activation of P2Y1 and P2Y2 nucleotide receptors by adenosine 5′-triphosphate analogues augmented nerve-mediated relaxation of human corpus cavernosum. Can. Urol. Assoc. J.,  2009, 3(4), 314-318.
[http://dx.doi.org/10.5489/cuaj.1127] [PMID:  19672446] 
[79] 
Le Duc, D.; Schulz, A.; Lede, V.; Schulze, A.; Thor, D.; Brüser, A.; Schöneberg, T. P2Y Receptors in immune response and inflammation. Adv. Immunol.,  2017, 136, 85-121.
[http://dx.doi.org/10.1016/bs.ai.2017.05.006] [PMID:  28950952] 
[80] 
Martínez-Ramírez, A.S.; Garay, E.; García-Carrancá, A.; Vázquez-Cuevas, F. G. The P2RY2 Receptor induces carcinoma cell migration and EMT through cross-talk with epidermal growth factor receptor. J. Cell. Biochem.,  2016, 117(4), 1016-1026.
[http://dx.doi.org/10.1002/jcb.25390] [PMID:  26443721] 
[81] 
Jin, H.; Eun, S.Y.; Lee, J.S.; Park, S.W.; Lee, J.H.; Chang, K.C.; Kim, H.J. P2Y2 receptor activation by nucleotides released from highly metastatic breast cancer cells increases tumor growth and invasion via crosstalk with endothelial cells. Breast Cancer Res.,  2014, 16(5), R77.
[http://dx.doi.org/10.1186/bcr3694] [PMID:  25156554] 
[82] 
Hickman, S.E.; Kingery, N.D.; Ohsumi, T.K.; Borowsky, M.L.; Wang, L.C.; Means, T.K.; El Khoury, J. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci.,  2013, 16(12), 1896-1905.
[http://dx.doi.org/10.1038/nn.3554] [PMID:  24162652] 
[83] 
Jäger, E.; Schulz, A.; Lede, V.; Lin, C-C.; Schöneberg, T.; Le Duc, D. Dendritic cells regulate GPR34 through mitogenic signals and undergo apoptosis in its absence. J. Immunol.,  2016, 196(6), 2504-2513.
[http://dx.doi.org/10.4049/jimmunol.1501326] [PMID:  26851221] 
[84] 
Elliott, M.R.; Chekeni, F.B.; Trampont, P.C.; Lazarowski, E.R.; Kadl, A.; Walk, S.F.; Park, D.; Woodson, R.I.; Ostankovich, M.; Sharma, P.; Lysiak, J.J.; Harden, T.K.; Leitinger, N.; Ravichandran, K.S. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature,  2009, 461(7261), 282-286.
[http://dx.doi.org/10.1038/nature08296] [PMID:  19741708] 
[85] 
Feng, C.; Mery, A.G.; Beller, E.M.; Favot, C.; Boyce, J.A. Adenine nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor. J. Immunol.,  2004, 173(12), 7539-7547.
[http://dx.doi.org/10.4049/jimmunol.173.12.7539] [PMID:  15585881] 
[86] 
Kaebisch, C.; Schipper, D.; Babczyk, P.; Tobiasch, E. The role of purinergic receptors in stem cell differentiation. Comput. Struct. Biotechnol. J.,  2014, 13, 75-84.
[http://dx.doi.org/10.1016/j.csbj.2014.11.003] [PMID:  26900431] 
[87] 
Conroy, S.; Kindon, N.; Kellam, B.; Stocks, M.J. Drug-like antagonists of P2Y receptors-from lead identification to drug development. J. Med. Chem.,  2016, 59(22), 9981-10005.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01972] [PMID:  27413802] 
[88] 
Maffrand, J-P. The story of clopidogrel and its predecessor, ticlopidine: Could these major antiplatelet and antithrombotic drugs be discovered and developed today? C. R. Chim.,  2012, 15(8), 737-743.
[http://dx.doi.org/10.1016/j.crci.2012.05.006] 
[89] 
Ding, Z.; Kim, S.; Dorsam, R.T.; Jin, J.; Kunapuli, S.P. Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood,  2003, 101(10), 3908-3914.
[http://dx.doi.org/10.1182/blood-2002-10-3027] [PMID:  12560222] 
[90] 
Ingall, A.H.; Dixon, J.; Bailey, A.; Coombs, M.E.; Cox, D.; McInally, J.I.; Hunt, S.F.; Kindon, N.D.; Teobald, B.J.; Willis, P.A.; Humphries, R.G.; Leff, P.; Clegg, J.A.; Smith, J.A.; Tomlinson, W. Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy. J. Med. Chem.,  1999, 42(2), 213-220.
[http://dx.doi.org/10.1021/jm981072s] [PMID:  9925726] 
[91] 
Douglass, J.G.; deCamp, J.B.; Fulcher, E.H.; Jones, W.; Mahanty, S.; Morgan, A.; Smirnov, D.; Boyer, J.L.; Watson, P.S. Adenosine analogues as inhibitors of P2Y12 receptor mediated platelet aggregation. Bioorg. Med. Chem. Lett.,  2008, 18(6), 2167-2171.
[http://dx.doi.org/10.1016/j.bmcl.2008.01.038] [PMID:  18276138] 
[92] 
Bryant, J.; Post, J.M.; Alexander, S.; Wang, Y-X.; Kent, L.; Schirm, S.; Tseng, J.L.; Subramanyam, B.; Buckman, B.; Islam, I.; Yuan, S.; Sullivan, M.E.; Snider, M.; Morser, J. Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (I): In vitro effects on platelets. Thromb. Res.,  2008, 122(4), 523-532.
[http://dx.doi.org/10.1016/j.thromres.2008.03.026] [PMID:  18495218] 
[93] 
Caroff, E.; Meyer, E.; Treiber, A.; Hilpert, K.; Riederer, M.A. Optimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y(12) antagonists for inhibition of platelet aggregation. Bioorg. Med. Chem. Lett.,  2014, 24(17), 4323-4331.
[http://dx.doi.org/10.1016/j.bmcl.2014.06.070] [PMID:  25113932] 
[94] 
Kortum, S.W.; Lachance, R.M.; Schweitzer, B.A.; Yalamanchili, G.; Rahman, H.; Ennis, M.D.; Huff, R.M.; TenBrink, R.E. Thienopyrimidine-based P2Y12 platelet aggregation inhibitors. Bioorg. Med. Chem. Lett.,  2009, 19(20), 5919-5923.
[http://dx.doi.org/10.1016/j.bmcl.2009.08.059] [PMID:  19748783] 
[95] 
Boldron, C.; Besse, A.; Bordes, M-F.; Tissandié, S.; Yvon, X.; Gau, B.; Badorc, A.; Rousseaux, T.; Barré, G.; Meneyrol, J.; Zech, G.; Nazare, M.; Fossey, V.; Pflieger, A.M.; Bonnet-Lignon, S.; Millet, L.; Briot, C.; Dol, F.; Hérault, J.P.; Savi, P.; Lassalle, G.; Delesque, N.; Herbert, J.M.; Bono, F.N. -[6-(4-butanoyl-5-methyl-1H-pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-indole-3-carboxamide (SAR216471), a novel intravenous and oral, reversible, and directly acting P2Y12 antagonist. J. Med. Chem.,  2014, 57(17), 7293-7316.
[http://dx.doi.org/10.1021/jm500588w] [PMID:  25075638] 
[96] 
Stagg, J.; Smyth, M.J. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene,  2010, 29(39), 5346-5358.
[http://dx.doi.org/10.1038/onc.2010.292] [PMID:  20661219] 
[97] 
Butler, M.; Sanmugalingam, D.; Burton, V.J.; Wilson, T.; Pearson, R.; Watson, R.P.; Smith, P.; Parkinson, S.J. Impairment of adenosine A3 receptor activity disrupts neutrophil migratory capacity and impacts innate immune function in vivo. Eur. J. Immunol.,  2012, 42(12), 3358-3368.
[http://dx.doi.org/10.1002/eji.201242655] [PMID:  23027555] 
[98] 
Ohta, A.; Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature,  2001, 414(6866), 916-920.
[http://dx.doi.org/10.1038/414916a] [PMID:  11780065] 
[99] 
Naganuma, M.; Wiznerowicz, E.B.; Lappas, C.M.; Linden, J.; Worthington, M.T.; Ernst, P.B. Cutting edge: critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J. Immunol.,  2006, 177(5), 2765-2769.
[http://dx.doi.org/10.4049/jimmunol.177.5.2765] [PMID:  16920910] 
[100] 
Lappas, C.M.; Rieger, J.M.; Linden, J. A2A adenosine receptor induction inhibits IFN-γ production in murine CD4+ T cells. J. Immunol.,  2005, 174(2), 1073-1080.
[http://dx.doi.org/10.4049/jimmunol.174.2.1073] [PMID:  15634932] 
[101] 
Erdmann, A.A.; Gao, Z-G.; Jung, U.; Foley, J.; Borenstein, T.; Jacobson, K.A.; Fowler, D.H. Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2-driven expansion in vivo. Blood,  2005, 105(12), 4707-4714.
[http://dx.doi.org/10.1182/blood-2004-04-1407] [PMID:  15746085] 
[102] 
Raskovalova, T.; Lokshin, A.; Huang, X.; Jackson, E.K.; Gorelik, E. Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase A isozyme I (PKA I). Immunol. Res.,  2006, 36(1-3), 91-99.
[http://dx.doi.org/10.1385/IR:36:1:91] [PMID:  17337770] 
[103] 
Raskovalova, T.; Lokshin, A.; Huang, X.; Su, Y.; Mandic, M.; Zarour, H.M.; Jackson, E.K.; Gorelik, E. Inhibition of cytokine production and cytotoxic activity of human antimelanoma specific CD8+ and CD4+ T lymphocytes by adenosine-protein kinase A type I signaling. Cancer Res.,  2007, 67(12), 5949-5956.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4249] [PMID:  17575165] 
[104] 
Fishman, P.; Bar-Yehuda, S.; Synowitz, M.; Powell, J.D.; Klotz, K.N.; Gessi, S.; Borea, P.A. Adenosine receptors and cancer. Handb. Exp. Pharmacol.,  2009, 193(193), 399-441.
[http://dx.doi.org/10.1007/978-3-540-89615-9_14] [PMID:  19639290] 
[105] 
Ohta, A.; Kini, R.; Ohta, A.; Subramanian, M.; Madasu, M.; Sitkovsky, M. The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front. Immunol.,  2012, 3, 190.
[http://dx.doi.org/10.3389/fimmu.2012.00190] [PMID:  22783261] 
[106] 
Zarek, P.E.; Huang, C.T.; Lutz, E.R.; Kowalski, J.; Horton, M.R.; Linden, J.; Drake, C.G.; Powell, J.D. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood,  2008, 111(1), 251-259.
[http://dx.doi.org/10.1182/blood-2007-03-081646] [PMID:  17909080] 
[107] 
Ohta, A.; Gorelik, E.; Prasad, S.J.; Ronchese, F.; Lukashev, D.; Wong, M.K.; Huang, X.; Caldwell, S.; Liu, K.; Smith, P.; Chen, J.F.; Jackson, E.K.; Apasov, S.; Abrams, S.; Sitkovsky, M. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl. Acad. Sci. USA,  2006, 103(35), 13132-13137.
[http://dx.doi.org/10.1073/pnas.0605251103] [PMID:  16916931] 
[108] 
Allard, B.; Pommey, S.; Smyth, M.J.; Stagg, J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin. Cancer Res.,  2013, 19(20), 5626-5635.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0545] [PMID:  23983257] 
[109] 
Beavis, P.A.; Milenkovski, N.; Henderson, M.A.; John, L.B.; Allard, B.; Loi, S.; Kershaw, M.H.; Stagg, J.; Darcy, P.K. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced anti-tumor T cell responses. Cancer Immunol. Res.,  2015, 3(5), 506-517.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0211] [PMID:  25672397] 
[110] 
Mittal, D.; Young, A.; Stannard, K.; Yong, M.; Teng, M.W.; Allard, B.; Stagg, J.; Smyth, M.J. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res.,  2014, 74(14), 3652-3658.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0957] [PMID:  24986517] 
[111] 
Beavis, P.A.; Henderson, M.A.; Giuffrida, L.; Mills, J.K.; Sek, K.; Cross, R.S.; Davenport, A.J.; John, L.B.; Mardiana, S.; Slaney, C.Y.; Johnstone, R.W.; Trapani, J.A.; Stagg, J.; Loi, S.; Kats, L.; Gyorki, D.; Kershaw, M.H.; Darcy, P.K. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J. Clin. Invest.,  2017, 127(3), 929-941.
[http://dx.doi.org/10.1172/JCI89455] [PMID:  28165340] 
[112] 
Sun, Y.; Huang, P. Adenosine A2B receptor: From cell biology to human diseases. Front Chem.,  2016, 4, 37.
[http://dx.doi.org/10.3389/fchem.2016.00037] [PMID:  27606311] 
[113] 
Kasama, H.; Sakamoto, Y.; Kasamatsu, A.; Okamoto, A.; Koyama, T.; Minakawa, Y.; Ogawara, K.; Yokoe, H.; Shiiba, M.; Tanzawa, H.; Uzawa, K. Adenosine A2b receptor promotes progression of human oral cancer. BMC Cancer,  2015, 15(1), 563.
[http://dx.doi.org/10.1186/s12885-015-1577-2] [PMID:  26228921] 
[114] 
Xiang, H.J.; Liu, Z.C.; Wang, D.S.; Chen, Y.; Yang, Y.L.; Dou, K.F. Adenosine A(2b) receptor is highly expressed in human hepatocellular carcinoma. Hepatol. Res.,  2006, 36(1), 56-60.
[http://dx.doi.org/10.1016/j.hepres.2006.06.008] [PMID:  16844405] 
[115] 
Mittal, D.; Sinha, D.; Barkauskas, D.; Young, A.; Kalimutho, M.; Stannard, K.; Caramia, F.; Haibe-Kains, B.; Stagg, J.; Khanna, K.K.; Loi, S.; Smyth, M.J. Adenosine 2B receptor expression on cancer cells promotes metastasis. Cancer Res.,  2016, 76(15), 4372-4382.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0544] [PMID:  27221704] 
[116] 
Allard, D.; Turcotte, M.; Stagg, J. Targeting A2 adenosine receptors in cancer. Immunol. Cell Biol.,  2017, 95(4), 333-339.
[http://dx.doi.org/10.1038/icb.2017.8] 
[117] 
Belguise, K.; Kersual, N.; Galtier, F.; Chalbos, D. FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells. Oncogene,  2005, 24(8), 1434-1444.
[http://dx.doi.org/10.1038/sj.onc.1208312] [PMID:  15608675] 
[118] 
Zhao, C.; Qiao, Y.; Jonsson, P.; Wang, J.; Xu, L.; Rouhi, P.; Sinha, I.; Cao, Y.; Williams, C.; Dahlman-Wright, K. Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer. Cancer Res.,  2014, 74(14), 3983-3994.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-3396] [PMID:  24830720] 
[119] 
Loi, S.; Dushyanthen, S.; Beavis, P.A.; Salgado, R.; Denkert, C.; Savas, P.; Combs, S.; Rimm, D.L.; Giltnane, J.M.; Estrada, M.V.; Sánchez, V.; Sanders, M.E.; Cook, R.S.; Pilkinton, M.A.; Mallal, S.A.; Wang, K.; Miller, V.A.; Stephens, P.J.; Yelensky, R.; Doimi, F.D.; Gómez, H.; Ryzhov, S.V.; Darcy, P.K.; Arteaga, C.L.; Balko, J.M. RAS/MAPK Activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: Therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin. Cancer Res.,  2016, 22(6), 1499-1509.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1125] [PMID:  26515496] 
[120] 
Liu, S.; Foulkes, W.D.; Leung, S.; Gao, D.; Lau, S.; Kos, Z.; Nielsen, T.O. Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Res.,  2014, 16(5), 432.
[http://dx.doi.org/10.1186/s13058-014-0432-8] [PMID:  25193543] 
[121] 
Ehrentraut, H.; Westrich, J.A.; Eltzschig, H.K.; Clambey, E.T. Adora2b adenosine receptor engagement enhances regulatory T cell abundance during endotoxin-induced pulmonary inflammation. PLoS One,  2012, 7(2)e32416
[http://dx.doi.org/10.1371/journal.pone.0032416] [PMID:  22389701] 
[122] 
Koscsó, B.; Csóka, B.; Kókai, E.; Németh, Z.H.; Pacher, P.; Virág, L.; Leibovich, S.J.; Haskó, G. Adenosine augments IL-10-induced STAT3 signaling in M2c macrophages. J. Leukoc. Biol.,  2013, 94(6), 1309-1315.
[http://dx.doi.org/10.1189/jlb.0113043] [PMID:  23922379] 
[123] 
García-Rocha, R.; Moreno-Lafont, M.; Mora-García, M.L.; Weiss-Steider, B.; Montesinos, J.J.; Piña-Sánchez, P.; Monroy-García, A. Mesenchymal stromal cells derived from cervical cancer tumors induce TGF-β1 expression and IL-10 expression and secretion in the cervical cancer cells, resulting in protection from cytotoxic T cell activity. Cytokine,  2015, 76(2), 382-390.
[http://dx.doi.org/10.1016/j.cyto.2015.09.001] [PMID:  26343835] 
[124] 
Wilson, J.M.; Ross, W.G.; Agbai, O.N.; Frazier, R.; Figler, R.A.; Rieger, J.; Linden, J.; Ernst, P.B. The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells. J. Immunol.,  2009, 182(8), 4616-4623.
[http://dx.doi.org/10.4049/jimmunol.0801279] [PMID:  19342636] 
[125] 
Arihara, F.; Mizukoshi, E.; Kitahara, M.; Takata, Y.; Arai, K.; Yamashita, T.; Nakamoto, Y.; Kaneko, S. Increase in CD14+HLA-DR -/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol. Immunother.,  2013, 62(8), 1421-1430.
[http://dx.doi.org/10.1007/s00262-013-1447-1] [PMID:  23764929] 
[126] 
Wilson, J.M.; Ross, W.G.; Agbai, O.N.; Frazier, R.; Figler, R.A.; Rieger, J.; Linden, J.; Ernst, P.B. The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells. J. Immunol.,  2009, 182(8), 4616-4623.
[http://dx.doi.org/10.4049/jimmunol.0801279] [PMID:  19342636] 
[127] 
Jin, D.; Fan, J.; Wang, L.; Thompson, L.F.; Liu, A.; Daniel, B.J.; Shin, T.; Curiel, T.J.; Zhang, B. CD73 on tumor cells impairs antitumor T-cell responses: A novel mechanism of tumor-induced immune suppression. Cancer Res.,  2010, 70(6), 2245-2255.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3109] [PMID:  20179192] 
[128] 
Jaakola, V-P.; Griffith, M.T.; Hanson, M.A.; Cherezov, V.; Chien, E.Y.; Lane, J.R.; Ijzerman, A.P.; Stevens, R.C. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science,  2008, 322(5905), 1211-1217.
[http://dx.doi.org/10.1126/science.1164772] [PMID:  18832607] 
[129] 
Jacobson, K.A.; Balasubramanian, R.; Deflorian, F.; Gao, Z.G. G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions. Purinergic Signal.,  2012, 8(3), 419-436.
[http://dx.doi.org/10.1007/s11302-012-9294-7] [PMID:  22371149] 
[130] 
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,  2013, 15(12), 1400-1409.
[http://dx.doi.org/10.1593/neo.131748] [PMID:  24403862] 
[131] 
Tabellini, G.; Borsani, E.; Benassi, M.; Patrizi, O.; Ricotta, D.; Caimi, L.; Lanzi, R.; Micheli, F.; Iorno, V.; Bettaglio, R.; Rezzani, R.; Rodella, L.F.; Parolini, S. Effects of opioid therapy on human natural killer cells. Int. Immunopharmacol.,  2014, 18(1), 169-174.
[http://dx.doi.org/10.1016/j.intimp.2013.11.015] [PMID:  24287448] 
[132] 
Al-Hashimi, M.; Scott, S.W.; Thompson, J.P.; Lambert, D.G. Opioids and immune modulation: more questions than answers. Br. J. Anaesth.,  2013, 111(1), 80-88.
[http://dx.doi.org/10.1093/bja/aet153] [PMID:  23794649] 
[133] 
Singleton, P.A.; Moss, J.; Karp, D.D.; Atkins, J.T.; Janku, F. The mu opioid receptor: A new target for cancer therapy? Cancer,  2015, 121(16), 2681-2688.
[http://dx.doi.org/10.1002/cncr.29460] [PMID:  26043235] 
[134] 
Stein, C.; Machelska, H. Modulation of peripheral sensory neurons by the immune system: Iimplications for pain therapy. Pharmacol. Rev.,  2011, 63(4), 860-881.
[http://dx.doi.org/10.1124/pr.110.003145] [PMID:  21969325] 
[135] 
Stein, C. Opioids, sensory systems and chronic pain. Eur. J. Pharmacol.,  2013, 716(1-3), 179-187.
[http://dx.doi.org/10.1016/j.ejphar.2013.01.076] [PMID:  23500206] 
[136] 
Katritch, V.; Cherezov, V.; Stevens, R.C. Structure-function of the G protein-coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol.,  2013, 53, 531-556.
[http://dx.doi.org/10.1146/annurev-pharmtox-032112-135923] [PMID:  23140243] 
[137] 
Pert, C.B.; Snyder, S.H. Opiate receptor: demonstration in nervous tissue. Science,  1973, 179(4077), 1011-1014.
[http://dx.doi.org/10.1126/science.179.4077.1011] [PMID:  4687585] 
[138] 
Lord, J.A.H.; Waterfield, A.A.; Hughes, J.; Kosterlitz, H.W. Endogenous opioid peptides: multiple agonists and receptors. Nature,  1977, 267(5611), 495-499.
[http://dx.doi.org/10.1038/267495a0] [PMID:  195217] 
[139] 
Kieffer, B.L.; Befort, K.; Gaveriaux-Ruff, C.; Hirth, C.G. The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc. Natl. Acad. Sci. USA,  1992, 89(24), 12048-12052.
[http://dx.doi.org/10.1073/pnas.89.24.12048] [PMID:  1334555] 
[140] 
Granier, S.; Manglik, A.; Kruse, A.C.; Kobilka, T.S.; Thian, F.S.; Weis, W.I.; Kobilka, B.K. Structure of the δ-opioid receptor bound to naltrindole. Nature,  2012, 485(7398), 400-404.
[http://dx.doi.org/10.1038/nature11111] [PMID:  22596164] 
[141] 
Thompson, A.A.; Liu, W.; Chun, E.; Katritch, V.; Wu, H.; Vardy, E.; Huang, X.P.; Trapella, C.; Guerrini, R.; Calo, G.; Roth, B.L.; Cherezov, V.; Stevens, R.C. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature,  2012, 485(7398), 395-399.
[http://dx.doi.org/10.1038/nature11085] [PMID:  22596163] 
[142] 
Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G.W.; Vardy, E.; Liu, W.; Thompson, A.A.; Huang, X.P.; Carroll, F.I.; Mascarella, S.W.; Westkaemper, R.B.; Mosier, P.D.; Roth, B.L.; Cherezov, V.; Stevens, R.C. Structure of the human κ-opioid receptor in complex with JDTic. Nature,  2012, 485(7398), 327-332.
[http://dx.doi.org/10.1038/nature10939] [PMID:  22437504] 
[143] 
Manglik, A.; Kruse, A.C.; Kobilka, T.S.; Thian, F.S.; Mathiesen, J.M.; Sunahara, R.K.; Pardo, L.; Weis, W.I.; Kobilka, B.K.; Granier, S. Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Nature,  2012, 485(7398), 321-326.
[http://dx.doi.org/10.1038/nature10954] [PMID:  22437502] 
[144] 
Cox, B.M.; Christie, M.J.; Devi, L.; Toll, L.; Traynor, J.R. Challenges for opioid receptor nomenclature: IUPHAR Review 9. Br. J. Pharmacol.,  2015, 172(2), 317-323.
[http://dx.doi.org/10.1111/bph.12612] [PMID:  24528283] 
[145] 
Dietis, N.; Rowbotham, D.J.; Lambert, D.G. Opioid receptor subtypes: Fact or artifact? Br. J. Anaesth.,  2011, 107(1), 8-18.
[http://dx.doi.org/10.1093/bja/aer115] [PMID:  21613279] 
[146] 
Lanier, L.L. NK cell recognition. Annu. Rev. Immunol.,  2005, 23(1), 225-274.
[http://dx.doi.org/10.1146/annurev.immunol.23.021704.115526] [PMID:  15771571] 
[147] 
Moretta, A.; Marcenaro, E.; Parolini, S.; Ferlazzo, G.; Moretta, L. NK cells at the interface between innate and adaptive immunity. Cell Death Differ.,  2008, 15(2), 226-233.
[http://dx.doi.org/10.1038/sj.cdd.4402170] [PMID:  17541426] 
[148] 
Juneja, R. Opioids and cancer recurrence. Curr. Opin. Support. Palliat. Care,  2014, 8(2), 91-101.
[http://dx.doi.org/10.1097/SPC.0000000000000056] [PMID:  24759319] 
[149] 
Mellon, R.D.; Bayer, B.M. Evidence for central opioid receptors in the immunomodulatory effects of morphine: review of potential mechanism(s) of action. J. Neuroimmunol.,  1998, 83(1-2), 19-28.
[http://dx.doi.org/10.1016/S0165-5728(97)00217-8] [PMID:  9610669] 
[150] 
Flores, L.R.; Dretchen, K.L.; Bayer, B.M. Potential role of the autonomic nervous system in the immunosuppressive effects of acute morphine administration. Eur. J. Pharmacol.,  1996, 318(2-3), 437-446.
[http://dx.doi.org/10.1016/S0014-2999(96)00788-1] [PMID:  9016936] 
[151] 
Singhal, P.C.; Sharma, P.; Kapasi, A.A.; Reddy, K.; Franki, N.; Gibbons, N. Morphine enhances macrophage apoptosis. J. Immunol.,  1998, 160(4), 1886-1893.
[PMID:  9469450] 
[152] 
Gupta, K.; Kshirsagar, S.; Chang, L.; Schwartz, R.; Law, P.Y.; Yee, D.; Hebbel, R.P. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res.,  2002, 62(15), 4491-4498.
[PMID:  12154060] 
[153] 
Singleton, P.A.; Lingen, M.W.; Fekete, M.J.; Garcia, J.G.N.; Moss, J. Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: Role of receptor transactivation. Microvasc. Res.,  2006, 72(1-2), 3-11.
[http://dx.doi.org/10.1016/j.mvr.2006.04.004] [PMID:  16820176] 
[154] 
Boehncke, S.; Hardt, K.; Schadendorf, D.; Henschler, R.; Boehncke, W.H.; Duthey, B. Endogenous μ-opioid peptides modulate immune response towards malignant melanoma. Exp. Dermatol.,  2011, 20(1), 24-28.
[http://dx.doi.org/10.1111/j.1600-0625.2010.01158.x] [PMID:  20955200] 
[155] 
Mathew, B.; Lennon, F.E.; Siegler, J.; Mirzapoiazova, T.; Mambetsariev, N.; Sammani, S.; Gerhold, L.M.; LaRiviere, P.J.; Chen, C.T.; Garcia, J.G.; Salgia, R.; Moss, J.; Singleton, P.A. The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth. Analg.,  2011, 112(3), 558-567.
[http://dx.doi.org/10.1213/ANE.0b013e31820568af] [PMID:  21156980] 
[156] 
Tegeder, I.; Grösch, S.; Schmidtko, A.; Häussler, A.; Schmidt, H.; Niederberger, E.; Scholich, K.; Geisslinger, G. G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. Cancer Res.,  2003, 63(8), 1846-1852.
[PMID:  12702572] 
[157] 
Wang, D.; Dubois, R.N. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene,  2010, 29(6), 781-788.
[http://dx.doi.org/10.1038/onc.2009.421] [PMID:  19946329] 
[158] 
Hangai, S.; Ao, T.; Kimura, Y.; Matsuki, K.; Kawamura, T.; Negishi, H.; Nishio, J.; Kodama, T.; Taniguchi, T.; Yanai, H. PGE2 induced in and released by dying cells functions as an inhibitory DAMP. Proc. Natl. Acad. Sci. USA,  2016, 113(14), 3844-3849.
[http://dx.doi.org/10.1073/pnas.1602023113] [PMID:  27001836] 
[159] 
Hata, A.N.; Breyer, R.M. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol. Ther.,  2004, 103(2), 147-166.
[http://dx.doi.org/10.1016/j.pharmthera.2004.06.003] [PMID:  15369681] 
[160] 
Chang, J.; Vacher, J.; Yao, B.; Fan, X.; Zhang, B.; Harris, R.C.; Zhang, M.Z. Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis. Oncotarget,  2015, 6(32), 33500-33511.
[http://dx.doi.org/10.18632/oncotarget.5589] [PMID:  26378024] 
[161] 
Chen, J.H.; Perry, C.J.; Tsui, Y-C.; Staron, M.M.; Parish, I.A.; Dominguez, C.X.; Rosenberg, D.W.; Kaech, S.M. Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat. Med.,  2015, 21(4), 327-334.
[http://dx.doi.org/10.1038/nm.3831] [PMID:  25799228] 
[162] 
Kashiwagi, E.; Inoue, S.; Mizushima, T.; Chen, J.; Ide, H.; Kawahara, T.; Reis, L.O.; Baras, A.S.; Netto, G.J.; Miyamoto, H. Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression. Br. J. Cancer,  2018, 118(2), 213-223.
[http://dx.doi.org/10.1038/bjc.2017.393] [PMID:  29123257] 
[163] 
Minakuchi, R.; Wacholtz, M.C.; Davis, L.S.; Lipsky, P.E. Delineation of the mechanism of inhibition of human T cell activation by PGE2. J. Immunol.,  1990, 145(8), 2616-2625.
[PMID:  1976699] 
[164] 
Sharma, S.; Yang, S-C.; Zhu, L.; Reckamp, K.; Gardner, B.; Baratelli, F.; Huang, M.; Batra, R.K.; Dubinett, S.M. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res.,  2005, 65(12), 5211-5220.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-0141] [PMID:  15958566] 
[165] 
Albu, D.I.; Wang, Z.; Huang, K-C.; Wu, J.; Twine, N.; Leacu, S.; Ingersoll, C.; Parent, L.; Lee, W.; Liu, D.; Wright-Michaud, R.; Kumar, N.; Kuznetsov, G.; Chen, Q.; Zheng, W.; Nomoto, K.; Woodall-Jappe, M.; Bao, X. EP4 Antagonism by E7046 diminishes Myeloid immunosuppression and synergizes with Treg-reducing IL-2-Diphtheria toxin fusion protein in restoring anti-tumor immunity. OncoImmunology,  2017, 6(8)e1338239
[http://dx.doi.org/10.1080/2162402X.2017.1338239] [PMID:  28920002] 
[166] 
Clark, P.; Rowland, S.E.; Denis, D.; Mathieu, M-C.; Stocco, R.; Poirier, H.; Burch, J.; Han, Y.; Audoly, L.; Therien, A.G.; Xu, D. MF498 [N-[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl-2-(2-methoxyphenyl)acetamide], a selective E prostanoid receptor 4 antagonist, relieves joint inflammation and pain in rodent models of rheumatoid and osteoarthritis. J. Pharmacol. Exp. Ther.,  2008, 325(2), 425-434.
[http://dx.doi.org/10.1124/jpet.107.134510] [PMID:  18287210] 
[167] 
Xu, S.; Zhang, Z.; Ogawa, O.; Yoshikawa, T.; Sakamoto, H.; Shibasaki, N.; Goto, T.; Wang, L.; Terada, N. An EP4 antagonist ONO-AE3-208 suppresses cell invasion, migration, and metastasis of prostate cancer. Cell Biochem. Biophys.,  2014, 70(1), 521-527.
[http://dx.doi.org/10.1007/s12013-014-9951-2] [PMID:  24744183] 
[168] 
Blouin, M.; Han, Y.; Burch, J.R. The Discovery of 4-1-[(2,5-Dimethyl-4-[4-(trifluoromethyl)benzyl]-3 thienylcarbonyl)amino] cyclopropylbenzoic acid (MK-2894), a potent and selective prostaglandin E2 subtype 4 receptor antagonist. J. Med. Chem.,  2010, 53(5), 2227-2238.
[http://dx.doi.org/10.1021/jm901771h] [PMID:  20163116] 
[169] 
Rausch-Derra, L.C.; Huebner, M.; Rhodes, L. Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. Am. J. Vet. Res.,  2015, 76(10), 853-859.
[http://dx.doi.org/10.2460/ajvr.76.10.853] [PMID:  26413822] 
[170] 
Goetzl, E.J.; Gräler, M.H. Sphingosine 1-phosphate and its type 1 G protein-coupled receptor: trophic support and functional regulation of T lymphocytes. J. Leukoc. Biol.,  2004, 76(1), 30-35.
[http://dx.doi.org/10.1189/jlb.1103567] [PMID:  14982946] 
[171] 
O’Mahony, L.; Akdis, M.; Akdis, C.A. Regulation of the immune response and inflammation by histamine and histamine receptors. J. Allergy Clin. Immunol.,  2011, 128(6), 1153-1162.
[http://dx.doi.org/10.1016/j.jaci.2011.06.051] [PMID:  21824648] 
[172] 
Gotwals, P.; Cameron, S.; Cipolletta, D.; Cremasco, V.; Crystal, A.; Hewes, B.; Mueller, B.; Quaratino, S.; Sabatos-Peyton, C.; Petruzzelli, L.; Engelman, J.A.; Dranoff, G. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat. Rev. Cancer,  2017, 17(5), 286-301.
[http://dx.doi.org/10.1038/nrc.2017.17] [PMID:  28338065] 
[173] 
Albu, D.I.; Verbel, D.; Huang, Y.; Kolber-Simonds, D.; Wang, Z.; Wang, X.; Dezso, Z.; Ingersoll, C.; Huang, K-C.; Hutz, J.; Woodall-Jappe, M.; Bao, X. Y. Specific inhibition of PGE2-EP4 signaling by E7046 promotes anti-tumor activity of checkpoint blockade agents through boosting cytotoxic T cell activity. Cancer Res.,  2017, 77, 4607-4607.
[http://dx.doi.org/DOI: 10.1158/1538-7445.AM2017-4607] 
[174] 
Ishida, T.; Ito, A.; Sato, F.; Kusumoto, S.; Iida, S.; Inagaki, H.; Morita, A.; Akinaga, S.; Ueda, R. Stevens-Johnson Syndrome associated with mogamulizumab treatment of adult T-cell leukemia/lymphoma. Cancer Sci.,  2013, 104(5), 647-650.
[http://dx.doi.org/10.1111/cas.12116] [PMID:  23360455] 
Rights & Permissions Print Cite
Article Metrics
51
7
3
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1568026619666190628115644	Print ISSN 1568-0266
Publisher Name Bentham Science Publisher	Online ISSN 1873-4294
Current Topics in Medicinal Chemistry

Recent Advances of Small Molecular Regulators Targeting G Protein- Coupled Receptors Family for Oncology Immunotherapy

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Related Articles

Abstract
