Small molecules for immunomodulation in cancer: A review

Anti-Cancer Agents in Medicinal Chemistry

Volumn 15, Issue 4, 2015, Pages 433-452

  Iyer, Vidhya V ^a  

^a VIT UNIVERSITY   (India)

Author keywords

Cancer immunomodulation; Immune cell recruitment; Inhibitor; Receptor antagonists; Small molecule; Target specific; Tumor microenvironment

Indexed keywords

ANTIBODY; CALCIUM ION; CELL SURFACE RECEPTOR; CHECKPOINT KINASE 2; CHEMOKINE RECEPTOR CXCR4; CYTOCHROME C; CYTOTOXIC AGENT; CYTOTOXIC AGENTINDOLEAMINE 2,3 DIOXYGENASE INHIBITOR; EMODIN; EPHRIN RECEPTOR ANTAGONIST; FOCAL ADHESION KINASE INHIBITOR; IMIQUIMOD; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTEGRIN; INTEGRIN RECEPTOR; INTEGRIN RECEPTOR ANTAGONIST; INTERLEUKIN 12; INTERLEUKIN 17; INTERLEUKIN 6; MEMBRANE BOUND CARBONIC ANHYDRASE IX INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN BCL 2; PROTEIN KINASE INHIBITOR; RETINOID RELATED ORPHAN RECEPTOR GAMMA ANTAGONIST; STAT PROTEIN; STROMAL CELL DERIVED FACTOR 1; TOLL LIKE RECEPTOR 7; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULAR CELL ADHESION MOLECULE 1; VITRONECTIN RECEPTOR; ANTINEOPLASTIC AGENT;

ARTICLE; CANCER IMMUNOTHERAPY; CELL PROLIFERATION; DOWN REGULATION; DRUG CONJUGATION; ENZYME ACTIVITY; HUMAN; IMMUNE DYSREGULATION; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; INTRACELLULAR SIGNALING; LIGAND BINDING; METASTASIS; MOLECULE; NEOPLASM; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROSTATE CANCER; TUMOR CELL; TUMOR MICROENVIRONMENT; ADAPTIVE IMMUNITY; ANIMAL; DRUG EFFECTS; DRUG RESISTANCE; IMMUNOLOGY; INNATE IMMUNITY; NEOPLASMS; PATHOLOGY;

ADAPTIVE IMMUNITY; ANIMALS; ANTINEOPLASTIC AGENTS; CELL PROLIFERATION; DRUG RESISTANCE, NEOPLASM; HUMANS; IMMUNITY, INNATE; IMMUNOMODULATION; NEOPLASMS; TUMOR MICROENVIRONMENT;

EID: 84929677570     PISSN: 18715206     EISSN: 18755992     Source Type: Journal    
DOI: 10.2174/1871520615666141210152128     Document Type: Article

References (203)

1. Muller, A.J.; Scherle, P.A. Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat. Rev. Cancer, 2006, 6, 613-625.
2. Miller, M.J.; Foy, K.C.; Kaumaya, P.T.P. Cancer Immunotherapy: Present status, Future perspective and a new paradigm of peptide immunotherapeutics. Dis. Med., 2013, 15(82), 166-176.
3. Hagemann, T.; Wilson, J.; Burke, F.; Kulbe, H.; Li, N.F.; Plueddemann, A.; Charles, K.; Gordon, S.; Balkwill, F.R. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J. Immunol., 2006, 176, 5023-5032.
4. Klinke, D.J. A multiscale systems perspective on cancer, immunotherapy and interleukin-12. Mol. Cancer, 2010, 9,242.
5. Colombo, M.P.; Trinchieri, G. Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev., 2002, 12, 155-168.
6. Nimmerjahn, F.; Ravetch, J.V. Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science, 2005, 310, 1510-1512.
7. A new strategy for immunotherapy of cancer. Available at: http://www.isracast. com/article.aspx?ID=1147.
8. Ben-Baruch, A. Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: Reciprocal tumor-microenvironment interactions. Breast Cancer Res., 2003, 5, 31-36.
9. Roswell Park Cancer Institute, CCSG Research Programs, Tumor immunology and immunotherapy. Available at: https://www. roswellpark.edu/research/ccsg-research-programs/tumorimmunology-and-immunotherapy (Accessed August 29, 2014).
10. Airoldi, I.; Cocco, C.; Giulani, N.; Ferrarini, M.; Colla, S.; Ognio, E.; Taverniti, G.; Di, C.E.; Cutrona, G.; Perfetti, V.; Rizzoli, V.; Ribatti, D.; Pistoia, V. Constitutive expression of IL-12R beta-2 on human multiple myeloma cells delineates a novel therapeutic target. Blood, 2008, 112, 750-759.
11. Pardoll, D.; Drake, C. Immunotherapy earns its spot in the ranks of cancer therapy. J. Exp. Med., 2012, 209, 201-209.
12. http://www.cancerconversations.com/cancer-immunotherapy.html
13. Von Mensdorff-Pouilly, S. in Encyclopedia of cancer, Manfred Schwab, Ed.; Springer Berlin Heidelberg, 2012; 2698-2704.
14. Teicher, B.A.; Chari, R.V.J. Antibody conjugate therapeutics: Challenges and potential. Clin. Cancer Res., 2011, 17, 6389-6397.
15. Drachman, J.G.; Senter, P.D. Antibody-drug conjugates: The chemistry behind empowering antibodies to fight cancer. Amer. Soc. Hematol. Book, 2013, 2013(1), 306-310.
16. Janthur, W.D.; Cantoni, N.; Mamot, C. Drug conjugates such as antibody drug conjugates (ADCs), immunotoxins and immunoliposomes challenge daily clinical practice. Int. J. Mol. Sci., 2012, 13, 16020-16045.
17. Mukherjee, S.; Ghosh, R.N.; Maxfield, F.R. Endocytosis. Physiol. Rev., 1997, 77, 759-803.
18. Schoen, M.; Bong, A.B.; Drewniok, C.; Herz, J.; Geilen, C.C.; Reifenberger, J.; Benninghoff, B.; Slade, H.B.; Gollnick, H.; Schoen, M.P. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J. Nat. Cancer Inst., 2003, 95, 1138-1149.
19. Miller, R.L.; Birmachu, W.; Gibson, S. Cytokine induction by imiquimod, preclinical results and pharmacology. Chemother. J. 1994, 4, 148-149.
20. Burns, R.P. Jr.; Ferbel, B.; Tomai, M.; Miller, R.; Gaspari, A.A. The imdazoquinolines, imiquimod and R-848, induce functional but not phenotypic, maturation of human epidermal Langerhans cells. Clin. Immunol., 2000, 94, 13-23.
21. Perdih, A.; Dolenc, M.S. Small molecule antagonists of integrin receptors. Curr. Med. Chem., 2010, 17, 2371-2392.
22. Hynes, R.O. Integrins: bidirectional, allosteric signaling machines. Cell, 2002, 110, 673-687.
23. Danen, E.H.J. Integrin signaling as a cancer drug target. ISRN Cell Biol., 2013, 135164, 2013, 1-14.
24. Legler, D.F.; Johnson-Leger, C.; Wiedle, G.; Bron, C.; Imhof, B. A. The alphavbeta3 integrin as a tumor homing ligand for lymphocytes. Eur. J. Immunol., 2004, 34, 1608-1616.
25. Piali, L.; Fichtel, A.; Terpe, H.J.; Imhof, B.A.; Gisler, R.H. Endothelial vascular cell adhesion molecule 1 expression is suppressed by melanoma and carcinoma. J. Exp. Med., 1995, 181, 811-816.
26. Griffioen, A.W.; Damen, C.A.; Martinotti, S.; Blijham, G.H.; Groenewegen, G. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: The role of angiogenic factors. Cancer Res., 1996, 56, 1111-1117.
27. Jinushi, M.; Chiba, S.; Baghdadi, M.; Kinoshita, I.; Dosaka-Akita, H.; Ito, K.; Yoshiyama, H.; Yagita, H.; Uede, T.; Takaoka, A. ATM-mediated DNA damage signals mediate immune escape through integrin-alphavbeta3-dependent mechanisms. Cancer Res., 2011, 72 (11), 56-65.
28. Marinelli, L.; Lavecchia, A.; Gottschalk, K.E.; Novellino, E.; Kessler, H. Docking studies on alphavbeta3 integrin ligands: Pharmacophore refinement and implications for drug design. J. Med. Chem., 2003, 46, 4393-4404.
29. Belvisi, L.; Bernardi, A.; Colombo, M.; Manzoni, L.; Potenza, D.; Scolastico, C.; Giannini, G.; Marcellini, M.; Riccioni, T.; Castorina, M.; LoGiudice, P.; Pisano, C. Targeting integrins: Insights into structure and activity of cyclic RGD pentapeptide mimics containing azabicycloalkane amino acids. Bioorg. Med. Chem., 2006, 14, 169-180.
30. Banfi, L.; Basso, A.; Damonte, G.; De Pellegrini, F.; Galatini, A.; Guanti, G.; Monfardini, I.; Riva, R.; Scapolla, C. Synthesis and biological evaluation of new conformationally based integrin ligands based on a tetrahydroazaninone scaffold. Bioorg. Med. Chem., 2007, 17, 1341-1345.
31. Gentuilucci, L.; Cardillo, G.; Squassabia, F.; Tolomelli, A.; Spampinato, S.; Sparta, A.; Baiula, M. Inhibition of cancer cell adhesion by heterchiral Pro-containing RGD mimetics. Bioorg. Med. Chem. Lett., 2007, 17, 2329-2333.
32. Carron, C.P.; Meyer, D.M.; Pegg, J.A.; Engleman, V.W.; Nickols, M.A.; Settle, S.L.; Westlin, W.F.; Ruminski, P.G.; Nickols, G.A. Peptidomimetic antagonist of the integrin alphavbeta3 inhibits leydig cell tumor growth and the development of hypercalcemia of malignancy. Cancer Res., 1998, 58, 1930-1935.
33. Rogers, T.E.; Ruminski, P.G.; Rico, J.G.; Lu, H.F.; Colson, P.J.; Awasthi, A.K.; Nagarajan, S.R.; Devadas, B.; Meyer, D.M.; Keene, J.L.; Settle, S.L.; Carron, C.P.; Engleman, V.W.; Freeman, S.K.; Shannon, K.E.; Knoerzer, D.L.; Westlin, M.M.; Nickols, M.A. In Abstracts of Papers, 221st ACS National Meeting, San Diego, 2001, MEDI-225.
34. Nagarajan, S.R.; Lu, H.F.; Gasiecki, A.F.; Khanna, I.K.; Parikh, M.D.; Desai, B.N.; Rogers, T.E.; Clare, M.; Chen, B.B.; Russell, M.A.; Keene, J.L.; Duffin, T.; Engleman, V.W.; Finn, M.B.; Freeman, S.K.; Klover, J.A.; Nickols, G.A.; Nickols, M.A.; Shannon, K.E.; Steininger, C.A.; Westlin, W.F.; Westlin, M.M.; Williams, M.L. Discovery of +(2-{4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl}-cyclcopropyl)acetic acid as potent and selective alphavbeta3 inhibitor: Design, synthesis and optimization. Bioorg. Med. Chem., 2007, 15, 3390-3412.
35. Aoudjit, F.; Vuori, K. Integrin signaling in cancer cell survival and chemoresistance. Chemother. Res. Pract., 2012, 2012, 1-16.
36. Kroemer, G.; Reed, J.C. Mitochondrial control of cell death. Nat. Med., 2000, 6 (5), 513-519.
37. Pribila, J.T.; Quale, A.C.; Mueller, K.L.; Shimizu, Y. Integrins and T cell-mediated immunity. Annu. Rev. Immunol., 2004, 22, 157-180.
38. Kamiguchi, K.; Tachibana, K.; Iwata, S.; Ohashi, Y.; Morimoto, C. Cas-L is required for beta1 integrin-mediated co-stimulation in human T cells. J. Immunol., 1999, 163(2), 563-568.
39. Gendron, S.; Couture, J.; Aoudjit, F. Integrin alpha2beta1 inhibits Fas-mediated apoptosis in T lymphocytes by protein phosphatase 2A-dependent activation of the MAPK/ERK pathway. J. Biol. Chem., 2003, 278(49), 48633-48643.
40. Boisvert, M.; Gendron S,; Chetoui, N.; Aoudjit, F. Alpha2beta1 integrin signaling auments T cell receptor-dependent production of interferon gamma in human T cells. Mol. Immunol., 2007, 44(15), 3732-3740.
41. Sterry, W.; Mielke, V.; Konter, U.; Kellner, I.; Boehncke, W.H. Role of beta1-integrins in epidermotropism of malignant T cells. Am. J. Pathol., 1992, 141(4), 855-860.
42. Hamilton, R.; Campbell, F.R. Immunochemical localization of extracellular materials in bone marrow of rats. Anat. Rec., 1991, 231(2), 218-224.
43. Hartmann, T.N.; Burger, J.A.; Glodek, A.; Fujii, N.; Burger, M. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene, 2005, 24 (27), 4462-4471.
44. Desgrosellier, J.S.; Cheresh, D.A. Integrins in cancer: Biological implications and therapeutic opportunities. Nat. Rev. Cancer, 2010, 10(1), 9-22.
45. Choi, S.; Vilaire, G.; Marcinkiewicz, C.; Winker, J.D.; Bennett, J.S.; DeGrado, W.F. Small molecule inhibitors of integrin alpha2beta1. J. Med. Chem., 2007, 50, 5457-5462.
46. Max, R.; Gerritsen, R.R.; Nooijen, P.T.; Goodman, S.L.; Sutter, A.; Keilholz, U.; Ruiter, D.J.; De Waal, R.M. Immunohistochemical analysis of integrin alphavbeta3 expression on tumor-associated vessels of human carcinomas. Int. J. Cancer, 1997, 71, 320-324.
47. Perron-Sierra, F.; Saint Dizier, D.; Bertrand, M.; Genton, A.; Tucker, G.C.; Casara, P. Substituted benzocyclohepentenes as potent and selective alphav integrin antagonists. Bioorg. Med. Chem. Lett., 2002, 12, 3291-3296.
48. Marugán, J.J.; Manthey, C.; Anaclerio, B.; Lafrance, L.; Lu, T.; Markotan, T.; Leonard, K.A.; Crysler, C.; Eisennagel, S.; Dasgupta, M.; Tomczuk, B. Design, synthesis, and biological evaluation of Novel Potent and Selective alphavbeta3/alphavbeta5 Integrin dual inhibitors with improved bioavailability. Selection of the molecular core. J. Med. Chem., 2005, 48, 926-934.
49. Raboisson, P.; Manthey, C.L.; Chaikin, M.; Lattanze, J.; Crysler, C.; Leonard, K.; Pan, W.; Tomczuk, B.E.; Marugán, J.J. Novel potent and selective alphavbeta3/alphavbeta5 integrin dual antagonists with reduced binding affinity for human serum albumin. Eur. J. Med. Chem., 2006, 41, 847-861.
50. Raboisson, P.; Desjarlais, R.L.; Reed, R.; Lattanze, J.; Chaikin, M.; Manthey, C.L.; Tomczuk, B.E.; Marugán, J.J. Identification of novel short chain 4-substituted indoles as potent alphavbeta3 antagonist using structure-based drug design. Eur. J. Med. Chem., 2007, 42, 334-343.
51. Letourneau, J.J.; Liu, J.; Ohlmeyer, M.H.; Riviello, C.; Rong, Y.; Li, H.; Appell, K.C.; Bansal, S.; Jacob, B.; Wong, A.; Webb, M.L. Synthesis and initial evaluation of novel, non-peptidic antagonists of the alphav-integrins alphavbeta3 and alphavbeta5. Bioorg. Med. Chem. Lett., 2009, 19, 353-355.
52. Beekman, K.W.; Colevas, A.D.; Cooney, K.; Dipaola R.; Dunn R.L.; Gross, M.; Keller, E.T.; Pienta, K.J.; Ryan, C.J.; Smith, D.; Hussain, M. Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: scientific rationale and study design, Clin. Genitourin. Cancer, 2006, 4(4), 299-302.
53. Ryu, J.; Kang, M.; Lee, M.S.; Kim, H.J.; Nam, S.H.; Song, H.E.; Lee, D.; Lee, J. W. Cross talk between the TM4SF5/Focal adhesion kinase and the Interleukin-6/STAT3 pathways promotes immune escape of human liver cancer cells. Mol. Cell Biol., 2014, 34(16), 2946-2960.
54. Weis, S.M.; Lim, S.T.; Lutu-Fuga, K.M.; Barnes, L.A.; Chen, X.L.; Gothert, J.R.; Shen, T.L.; Guan, J.L.; Schlaepfer, D.D.; Cheresh, D.A. Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK. J. Cell Biol., 2008, 181(1), 43-50.
55. Roberts, W.G.; Ung, E.; Whalen, P.; Cooper, B.; Hulford, C.; Autry, C.; Richter, D.; Emerson, E.; Lin, J.; Kath, J.; Coleman, K.; Yao, L.; Martinez-Alsina, L.; Lorenzen, M.; Berliner, M.; Luzzio, M.; Patel, N.; Schmitt, E.; LaCreca, S.; Jani, J.; Wessel, M.; Marr, E.; Griffor, M.; Vaidos, F. Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res., 2008, 68(6), 1935-1944.
56. McDonald, P.C.; Winum, J.Y.; Supuran, C.T.; Dedhar, S. Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget, 2012, 3(1), 84-97.
57. Rodriguez, A.; Sexon, W. J. Management of locally advanced renal cell carcinoma. Cancer Contr., 2006, 13 (3), 199-210.
58. Lou, Y.; McDonald, P.C.; Oloumi, A.; Chia, S.; Ostlund, C.; Ahmadi, A.; Kyle, A.; auf dem Keller, U.; Leung, S.; Hunstman, D.; Clarke, B.; Sutherland, B.W.; Waterhouse, D.; Bally, M.; Roskelly, C.; Overall, C.M.; Minchinton, A.; Pacchiano, F.; Carta, F.; Scozzofava, A.; Tousini, N.; Winum, J.Y.; Supuran, C.T.; Dedhar, S. Targeting tumor hypoxia: Suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res., 2011, 71, 3364-3376.
59. McIntyre, A.; Patiar, S.; Wigfield, S.; Li, J.L.; Ledaki, I.; Turley, H.; Leek, R.; Snell, C.; Gatter, K.; Sly, W.S.; Vaughan-Jones, R.D.; Swietach, P.; Harris, A.L. Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy. Cancer Res., 2012, 18, 3100-3111.
60. Dubois, L.; Peeters, S.; Lieuwes, N.G.; Geusens, N.; Thiry, A.; Wigfield, S.; Carta, F.; Mcintyre, A.; Scozzofova, A.; Dogne, J.M.; Supuran, C.T.; Harris, A.L.; Masereel, B.; Lambin, P. Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. Radiother. Oncol., 2011, 99, 424-431.
61. Murelli, R.P.; Zhang, A.X.; Michel, J.; Jorgensen, W.L.; Spiegel, D.A. Chemical control over immune recognition: A class of antibody-recruiting small molecules (ARMs) that target prostate cancer. J. Am. Chem. Soc., 2009, 131(47), 17090-17092.
62. Holmes, E.H.; Greene, T.G.; Tino, W.T.; Boynton, A.L.; Aldape, H.C.; Misrock, S.L.; Murphy, G.P. Analysis of glycosylation of prostate-specific membrane antigen derived from LNCaP cells, prostatic carcinoma tumors, and serum from prostate cancer patients. Prostate Suppl., 1996, 7, 25-29.
63. Rowe, D.S; Anderson, S.G.; Skegg, J. In: Immunoglobulins; Merle, E. Ed.; National Academy of Sciences Press: Washington, D.C., p 361.
64. Slusher, B.S.; Vornov, J.J.; Thomas, A.G.; Hurn, P.D.; Harukuni, I.; Bhardwaj, A.; Traystman, R.J.; Robinson, M.B.; Britton, P.; Lu, X.C.; Tortella, F.C.; Wozniak, K.M.; Yudkoff, M.; Potter, B.M.; Jackson, P.F. Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nat. Med., 1999, 5(12), 1396-1402.
65. Kozikowski, A.P.; Zhang, J.; Nan, F.; Petukhov, P.A.; Grajkowska, E.; Wroblewski, J.T.; Yamamoto, T.; Bzdega, T.; Wroblewska, B.; Neale, J.H. Synthesis of urea-based inhibitors as active site probes of glutamate carboxypeptidase II: Efficacy as analgesic agents. J. Med. Chem., 2004, 47, 1729-1738.
66. Barinka, C.; Rovenska, M.; Mlcochova, P.; Hlouchova, K.; Plechanovova, A.; Majer, P.; Tsukamoto, T.; Slusher, B.S.; Konvalinka, J.; Lubkowski, J. Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II. J. Med. Chem., 2007, 50, 3267-3273.
67. James, L.C.; Roversi, P.; Tawfik, D.S. Antibody multispecificity mediated by conformational diversity. Science, 2003, 299(5611), 1362-1367.
68. Wells, S.; Menor, S.; Hespenheide, B.; Thorpe, M.F. Constrained geometric simulation of diffusive motion in proteins. Phys. Biol., 2005, 2(4), S127-136.
69. Natarajan, A.; Du, W.; Xiong, C.Y.; DeNardo, G.L.; Denardo, S. J.; Gervay-Haque, J. Construction of di-scFv through a trivalent alkyne-azide 1,3-dipolar cycloaddition. Chem. Commun., 2007, 7, 695-697.
70. Zhu, X.; Wang, Y.; Yang, Y.; Yang, R.; Zhu, B.; Zhang, Y.; Lin, Y.; Lu, Y.; Li, X.; O' Byrne, K.T. Suppression of lipopolysaccharide-induced upregulation of toll-like receptor 4 by emodin in mouse proximal tubular epithelial cells. Mol. Med. Reports, 2012, 6,493-500.
71. Manu, K.A.; Shanmugam, M.K.; Ong, T.H.; Subramaniam, A.; Siveen, K.S.; Perumal, E.; Samy, R.P.; Bist, P.; Lim, L.H.K.; Prem Kumar, A.; Hui, K.M.; Sethi, G. Emodin suppresses migration and invasion through the modulation of CXCR4 expression in an orthotopic model of human hepatocellular carcinoma. PLoSOne, 2013, 8(3), eS7015.
72. Meng, G.; Liu, Y.; Lou, C.; Yang, H. Emodin suppresses lipopolysaccharide-induced pro-inflammatory responses and NFkappa B activation by disrupting lipid rafts in CD14-negative endothelial cells. Br. J. Pharmacol., 2010, 161, 1628-1644.
73. Zhang, W.; Li, H.; Bu, H.; Chen, H.; Tong, H.; Liu, D.; Guo, H.; Lin, S. Emodin inhibits the differentiation and maturation of dendritic cells and increases the production of regulatory T cells. Int. J. Mol. Med., 2012, 29, 159-164.
74. Xiao, S.; Yosef, N.; Yang, J.; Wang, Y.; Zhou, L.; Zhu, C.; Wu, C.; Baloglu, E.; Schmidt, D.; Ramesh, R.; Lobera, M.; Sundrud, M.S.; Tsai, P.; Xiang, Z.; Wang, J.; Xu, Y.; Lin, X.; Kretschmer, K.; Rahl, P.B.; Young, R.A.; Zhong, Z.; Hafler, D.A.; Regev, A.; Ghosh, S.; Marson, A.; Kuchroo, V.K. Small-molecule ROR gamma t antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity, 2014, 40, 477-489.
75. Paulos, C.M.; Nelson, M.H.; Yu, X.Z. Th17 cells in cancer. In: Tumor-induced immune suppression: Mechanisms and therapeutic reversal; gabrilovich, D.I; Hurwitz, A.A. (Eds.); Springer Science +Business Media, LLC 2014; XIV, pp. 37-46.
76. Hou, D.Y.; Muller, A.J.; Sharma, M.D.; DuHadaway, J.; Banerjee, T.; Johnson, M.; Mellor, A.L.; Prendergast, G.C.; Munn, D.H. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res., 2007, 67, 792-801.
77. Baban, B.; Chandler, P.R.; Sharma, M.D.; Pihkala, J.; Koni, P.A.; Munn, D.H.; Mellor, A.L. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol., 2009, 183(4), 2475-2483.
78. Noberini, R.; Koolpe, M.; Peddibhotla, S.; Dahl, R.; Su, Y.; Cosford, N.D.P.; Roth, G.P.; Pasquale, E.B. Small molecules can selectively inhibit ephrin binding to the ephA4 and EphA2 receptors. J. Biol. Chem. 2008, 283, 29461-29472.
79. Koolpe, M.; Burgess, R.; Dail, M.; Pasquale, E.B. EphB receptorbinding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J. Biol. Chem., 2005, 280, 17301-17311.
80. Caliguiri, M.; Molz, L.; Liu, Q.; Kaplan, F.; Xu, J.P.; Majeti, J.Z.; Ramos-Kelsey, R.; Murthi, K.; Lievens, S.; Tavernier, J.; Kley, N. MASPIT: Three-hybrid trap for quantitative proteome fingerprinting of small molecule-protein interactions in mammalian cells. Chem. Biol., 2006, 13(7), 711-722.
81. Tandon, M.; Vemula, S. V.V.; Mittal, S.K. Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Exp. Opin. Ther. Targ., 2011, 15(1), 31-51.
82. Freywald, A.; Sharfe, N.; D'E. Miller, C.; Rashotte, C.; Roifman, C.M. EphA receptors inhibit anti-CD3-induced apoptosis in thymocytes. J. Immunol., 2006, 176, 4066-4074.
83. Huang, F.; Reeves, K.; Han, X.; Fairchild, C.; Platero, S.; Wong, T.W.; Lee, F.; Shaw, P.; Clark, E. Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: Rationale for patient selection. Cancer Res., 2007, 67, 2226-2238.
84. Petty, A.; Myshkin, E.; Qin, H.; Guo, H.; Miao, H.; Tochtrop, G. P.; Hsieh, J.T.; Page, P.; Liu, L.; Lindner, D. J.; Acharya, C.; MacKerell, A.D. Jr.; Ficker, E.; Song, J.; Wang, B. A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo. PLoS One, 2012, 7(8), e42120.
85. Wang, S.; Placzek, W.J.; Stebbins, J.L.; Mitra, S.; Noberini, R.; Koolpe, M.; Zhang, Z.; Dahl, R.; Pasquale, E.B.; Pellecchia, M. A novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells. J. Med. Chem., 2012, 55(5), 2427-2436.
86. Duggineni, S.; Mitra, S.; Noberini, R.; Han. X.; Lin, N.; Xu, Y.; Tian, W.; An, J.; Pasquale, E.B.; Huang, Z. Design, synthesis and characterization of novel small molecular inhibitors of ephrin-B2 binding to EphB4. Biochem. Pharmacol., 2013, 85(4).
87. Ott, P.A.; Adams, S. Small-molecule protein kinase inhibitors and their effects on the immune system: implications for cancer treatment. Immunotherapy, 2011, 3(2), 213-227.
88. Guha, M.; Mackman, N. The phosphatidylinositol 3-kinase-AKT pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J. Biol. Chem., 2002, 277(35), 32124-32132.
89. Lu, H.T.; Yang, D.D.; Wysk, M.; Gatti, E.; Mellman, I.; Davis, R.J.; Flavell, R.A. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J., 1999, 18(7), 1845-1857.
90. Sato, K.; Nagayama, H.; Tadokoro, K.; Juji, T.; Takahashi, T.A. Extracellular signal-regulated kinase, stress-activated protein kinase/c-Jun N-terminal kinase, and p38 MAPK are involved in IL-10-mediated selective repression of TNF-alpha-induced activation and maturation of human peripheral blood monocyte-derived dendritic cells. J. Immunol., 1999, 162(7), 3865-3872.
91. Arrighi, J.F.; Rebsamen, M.; Rousset, F.; Kindler, V. Jauser, C. A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers. J. Immunol., 2001, 166(6), 3837-3845.
92. Dong, C.; Davis, R.J.; Flavell, R. A. MAP kinases in the immune response. Annu. Rev. Immunol., 2002, 20, 55-72.
93. Tan, A.H.; Lam, K.P. Pharmacologic inhibition of MEK-ERK signaling enhances Th17 differentiation. J. Immunol., 2010, 184(4), 1849-1857.
94. Gabrilovich, D.I.; Chen, H.L.; Girgis, K.R.; Cunningham, H.T.; Meny, G.M.; Nadaf, S.; Kavanaugh, D.; Carbone, D.P. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med., 1996, 2(10), 1096-1103.
95. Seliger, B.; Kiessling, R. The two sides of HER2/neu: Immune escape versus surveillance. Trends Mol. Med., 2013, 19(11), 677-684.
96. Marmor, M.D.; Skaria, K.B.; Yarden, Y. Signal transduction and oncogenesis by ErbB/HER receptors. Int. J. Rad. Oncol. Biol. Phys., 2004, 58(3), 903-913.
97. Wilhelm, S.M.; Carter, C.; Tang, I.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M.; Cao, Y.; Shujath, J.; Gawlak, S.; Eveleigh, D.; Rowley, B.; Liu, L.; Adnane, L.; Lynch, M.; Auclair, D.; Taylor, I.; Gedrich, R.; Voznesensky, A.; Riedl, B.; Post, L.E.; Bollag, G.; Trail, P.A. Bay 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res., 2004, 64(19), 7099-7109.
98. Escudier, B.; Eisen, T.; Stadler, W.M.; Szczylik, C.; Oudard, S.; Siebels, M.; Negrier, S.; Chevreau, C.; Solska, E.; Desai, A.A.; Rolland, F.; Demkov, T.; Hutson, T.E.; Gore, M.; Freeman, S.; Schwartz, B.; Shan, M.; Simantov, R.; Bukowski, R.M. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med., 2007, 356(2), 125-134.
99. Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; de Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A.; Schwartz, M.; Porta, C.; Zeuzem, S.; Bolondi, L.; Greten, T.F.; Galle, P.R.; Seltz, J.F.; Borbath, I.; Haussinger, D.; Giannaris, T.; Shan, M.; Moscovici, M.; Voliotis, D.; Bruix, J. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med., 2008, 359(4), 378-390.
100. Hipp, M.M.; Hilf, N.; Walter, S.; Werth, D.; Brauer, K.M.; Radsak, M.P.; Weinschenk, T.; Singh-Jasuja, H.; Brossart, P. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood, 2008, 111(12), 5610-5620.
101. Alfaro, C.; Suarez, N.; Gonzalez, A.; Solano, S.; Erro, L.; Dubrot, J.; Palazon, A.; Hervas-Stubbs, S.; Gurpide, A.; Lopez-Picazo, J.M.; Grande-Pulido, E.; Melero, I.; Perez. Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. Br. J. Cancer, 2009, 100(7), 1111-1119.
102. Dietz, A.B.; Souan, L.; Knutson, G.J.; Bulur, P.A.; Litzow, M.R.; Vuk-Pavlovic, S. Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood, 2004, 104 (4), 1094-1099.
103. Seggewiss, R.; Lore, K.; Greiner, E.;Magnusson, M.K.; Price, D.A.; Douek, D.C.; Dunbar, C.E.; Wiestner, A. Imatinib inhibits Tcell receptor-mediated T-cell proliferation and activation in a dosedependent manner. Blood, 2005, 105(6), 2473-2479.
104. Larmonier, N.; Janikashvili, N.; Lacasse, C.J.; Larmonier, C.B.; Cantrell, J.; Situ, E.; Lundeen, T.; Bonnotte, B.; Katsanis, E. Imatinib mesylate inhibits CD4+ CD25+ regulatory T-cell activity and enhances active immunotherapy against BCR-ABL tumors. J.Immunol., 2008, 181(10), 6955-6963.
105. Boissel, N.; Rousselor, P.; Raffoux, E.; Cayuela, J.M.; Soulier, J.; Mooney, N.; Charron, D.; Dombret, H.; Toubert, A.; Rea, D. Imatinib mesylate minimally affects BCR-ABL and normal monocyte-derived dendritic cells but strongly inhibits T-cell expansion despite reciprocal dendritic cell-T-cell activation. J. Leukoc. Biol., 2006, 79 (4), 747-756.
106. Wehner, R.; Wendisch, M.; Schakel, K.; Bornhauser, M.; Platzbecker, U.; Mohr, B.; Temme, A.; Bachmann, M.; Rieber, E.P.; Schmitz, M. Imatinib mesylate does not impair the immunogenicity of human myeloid blood dendritic cells. Leukemia, 2006, 20 (9), 1629-1232.
107. Mohty, M.; Jourdan, E.; Mami, N.B.; Vey, N.; Damaj, G.; Blaise, D.; Isnardon, D.; Olive, D.; Gaugler, B. Imatinib and plasmacytoid dendritic cell function in patients with chronic myeloid leukemia. Blood, 2004, 103(12), 4666-4668.
108. Wang, H.; Cheng, F.; Cuenca, A.; Horna, P.; Zheng, Z.; Bhalla, K.; Sotomayor, E.M. Imatinib mesylate (STI-571) enhances antigenpresenting cell function and overcomes tumor-induced CD4+ T-cell tolerance. Blood, 2005, 105 (3), 1135-1143.
109. Finke, J.H.; Rini, B.; Ireland, J.; Rayman, P.; Richmond, A.; Golshayan, A.; Wood, L.; Elson, P.; Garcia, J.; Dreicer, R.; Bukowski, R. Sunitinib reverses type-I immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin. Cancer Res., 2008, 14(20), 6674-6682.
110. Wongkajomsilp, W.; Wamanattajinda, V.; Kasetsinsombat, K.; Duangsa-ard, S.; Sa-ngiamsunotorn, K.; Hongeng, S.; Maneechotesuwan, K. Sunitinib indirectly enhanced anti-tumor cytotoxicity of cytokine-induced killer cells and CD3+ CD56+ subset through the co-culturing dendritic cells. PLoS ONE, 2013, 8(11), e78980.
111. Christofori, G. Changing neighbours, changing behaviour: Cell adhesion molecule-mediated signaling during tumour progression. EMBO J., 2003, 22(10), 2318-2323.
112. Cavallaro, U.; Christofori, G. Cell adhesion in tumor invasion and metastasis: Loss of the glue is not enough. Biochim. Biophys. Acta, 2001, 1552, 39-45.
113. Mamessier, E.; Sylvain, A.; Thibult, M.L.; Houvenaeghel, G.; Jacquemier, J.; Castellano, R.; Goncalves, A.; Andre, P.; Romagne, F.; Thibault, G.; Viens, P.; Birnbaum, D.; Bertucci, F.; Moretta, A.; Olive, D. Human breast cancer cells enhance self tolerance by promoting evasion from NKcell antitumor immunity. J. Clin. Invest., 2011, 121(9), 3609-3622.
114. Wischhusen, J.; Jung, G.; Radovanovic, I.; Beier, C.; Steinbach, J.P.; Rimner, A.; Huang, H.; Shculz, J.B.; Ohgaki, H.; Aguzzi, A.; Rammensee, H.G.; Weller, M. Identification of CD7-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma. Cancer Res., 2002, 62, 2592-2599.
115. Garcia, P.; De Heredia, A.B.; Bellon, T.; Carpio, E.; Llano, M.; Caparros, E.; Aparicio, P.; Lopez-Botet, M. Signalling via CD70, a member of the TNF family, regulates T cell functions. J. Leukocyte Biol., 2004, 76, 263-270.
116. Fujimoto, M.; Poe, J.C.; Hasegawa, M.; Tedder, T.F. CD19 regulates intrinsic B lymphocyte signal transduction and activation through a novel mechanism of processive amplification. Immunol. Res., 2000, 22, 2-3, 281-298.
117. Sato, S.; Ono, N. Steeber, D.A.; Pisetsky, D.S.; Tedder, T.F. CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J. Immunol., 1996, 157, 4371-4378.
118. Tedder, T.F.; Inaoki, M. Sato, S. The CD19/21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity. Immunity, 1997, 6, 107-118.
119. Lankester, A.C.; van Schijndel G.M.W.; Rood, P.M.L.; Verhoeven, A.J.; van Lier, R.A.W. B cell antigen receptor cross-linking induced tyrosine phosphorylation and membrane translocation of a multimeric Shc complex that is augmented by CD19 co-ligation. Eur. J. Immunol., 1994, 24, 2818-2825.
120. Tooze, R.M.; Doody, G.M.; Fearon, D.T. Counterregulation by the coreceptors CD19 and CD22 of MAP kinase activation by membrane immunoglobulin. Immunity, 1997, 7, 59-67.
121. Coiffier, B.; Thieblemont, C.; De Guibert, S.; Dupuis, J.; Ribrag, V.; Bouabdallah, R.; Morschhauser, F.; Cartron, G.; Le Gouill, S.; Casasnovas, O.; Holte, H.; Hatteville, L.; Zilocchi, C.; Oprea, C.; Tilly, H. Phase II study of anti-CD19 antibody drug conjugate (SAR3419) in combination with rituximab: Clinical activity and safety in patients with relapsed/refractory diffuse large B-cell lymphoma (NCT01470456). Blood, 2013, 122(21), 4395-4395.
122. Hombach, A.; Muche, J.M.; Gerken, M.; Gellrich, S.; Heuser, C.; Pohl, C.; Sterry, W.; Abken, H. T cells engrafted with a recombinant anti-CD30 receptor target autologous CD30+ cutaneous lymphoma cells. Gene Ther., 2001, 8, 891-895.
123. Ellis, T.M. et al. CD30 is a signal transducing molecule that defines a subset of human activated CD45RO+ T cells. J. Immunol., 1993, 151, 2380-2389.
124. Kennedy, M.K.; Willis, C.R.; Armitage, R.J. Deciphering CD30 ligand biology and its role in humoral immunity. Immunology, 2006, 118,143-152.
125. Hansen, H.P.; Dietrich, S.; Kisseleva, T.; Mokros, T.; Mentlein, R.; Lange, H.H.; Murphy, G.; Lemke, H. CD30 shedding from Karpas 299 lymphoma cells is mediated by TNF-alpha-converting enzyme. J. Immunol., 2000, 165, 6703-6709.
126. Cerutti, A.; Schaffer, A.; Goodwin, R.G.; Shah, S.; Zan, H.; Ely, S.; Casali, P. Engagement of CD153 (CD30 ligand) by CD30 T cell inhibits class switch DNA recombination and antibody production in human IgD+ IgM+ B cells. J. Immunol., 2000, 165, 786-794.
127. Foyil, K.V.; Bartlett, N.L. Anti-CD30 antibodies for Hodgkin lymphoma. Curr. Hematol. Malig. Rep., 2010, 5(3), 140-147.
128. Chen, X.; Soma, L.A.; Fromm, J.R. Targeted therapy for Hodgkin lymphoma and systemic anaplastic large cell lymphoma: Focus on brentuximab vedotin. Oncol. Targ. Ther., 2014, 7, 45-56.
129. Cantor, J.M.; Ginsberg, M.H. CD98 at the crossroads of adaptive immunity and cancer. J. Cell Sci., 2012, 125, 1373-1382.
130. Feral, C.C.; Zijlstra, A.; Tlcachenko, E.; Prager, G.; Gardel, M.L.; Slepak, M.; Ginsberg, M.H. CD98hc (SLC3A2) participates in fibronectin matrix assembly by mediating integrin signaling. J. Cell Biol., 2007, 178,701-711.
131. Holte, H.; Davies, C.D.; Kvaloy, S.; Smeland, E.B.; Foss-Abrahamsen, A.; Kaalhus, O.; Marton, P.F.; Godal, T. The activation-associated antigen 4F2 predicts patient survival in lowgrade B-cell lymphomas. Int. J. Cancer, 1987, 39, 590-594.
132. Esteban, F.; Ruiz-Cabello, F.; Concha, A.; Perez Ayala, M.; Delgado, M.; Garrido, F. Relationship of 4F2 antigen with local growth and metastatic potential of squamous cell carcinoma of the larynx. Cancer, 1990, 66, 1493-1498.
133. Verrey, F. System L: Heteromeric exchangers of large, neutral amino acids involved in directional transport. Pflugers Arch., 2003, 445, 529-533.
134. Araujo, C.; Marques, H.; Fernandes, J.C.; Pardal, A.; Brito, C. Cutaneous plasmacytomas secondary to nonsecretory multiple myeloma. J. Dermatol. Clin. Res., 2014, 2 (3), 1022-1026.
135. Bologna-Molina, R.; Gonzalez-Gonzalez, R.; Mosqueda-Taylor, A.; Molina-Frechero, N.; Damian-Matsumura, P.; Dominguez-Malagon, H. Expression of syndecan-1 in papillary carcinoma of the thyroid with extracellular invasion. Arch. Med. Res., 2010, 41, 33-37.
136. Nikolova, V.; Koo, C.Y.; Ibrahim, S.A.; Wang, Z.; Spillmann, D.; Dreier, R.; Kelsch, R.; Fischgrabe, J.; Smollich, M.; Rossi, L.H.; Sibrowski, W.; Wulfing, P.; Kiesel, L.; Yip, G.W.; Gotte, M. Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression. Carcinogenesis, 2009, 30 (3), 397-407.
137. Maric, G.; Rose, A.A.N.; Annis, M.G.; Siegel, P.M. Glycoprotein non-metastatic b (GPNMB): A metastatic mediator and emerging therapeutic target in cancer. Oncol. Targ. Ther., 2013, 6, 839-852.
138. Rose, A.A.; Annis, M.G.; Dong, Z.; Pepin, F.; Hallett, M.; Park, M.; Siegel, P.M. ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties. PLoS One, 2010, 5(8), e12093.
139. Kuan, C.T.; Wakiya, K.; Dowell, J.M.; Herndon, J.E. 2nd; Reardon, D.A.; Graner, M.W.; Riggins, G.J.; Wikstrand, C.J.; Bigner, D.D. Glycoprotein nonmetastatic melanoma protein, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin. Cancer Res., 2006, 12(7 Pt 1), 1970-1982.
140. Qian, X.; Mills, E.; Torgov, M.; LaRochelle, W.J.; Jeffers, M. Pharmacologically enhanced expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE antibodydrug conjugate. Mol. Oncol., 2008, 2(1), 81-93.
141. Baechner, D.; Schroder, D.; Gross, G. mRNA expression of the murine glycoprotein (transmembrane) nmb (Gpnmb) gene is linked to the developing retinal pigment epithelium and iris. Brain Res. Gene Exp. Patterns, 2002, 1 (3-4), 159-165.
142. Selim, A.A. Osteoactivin bioinformatic analysis: Prediction of novel functions, structural features, and modes of action. Med. Sci. Monit., 2009, 15(2), MT19-MT33.
143. Shikano, S.; Bonkobara, M.; Zukas, P.K.; Ariizumi, K. Molecular cloning of a dendritic cell-associated transmembrane protein, DCHIL, that promotes RGD-dependent adhesion of endothelial cells through recognition of heparin sulfate proteoglycan. J. Biol. Chem., 2001, 276(11), 8125-8134.
144. Furochi, H.; Tamura, S.; Mameoka, M. Yamada, C.; Ogawa, T.; Hirasaka, K.; Okumura, Y.; Imagawa, T.; Oguri, S.; Ishidoh, K.; Kishi, K.; Higashiyama, S.; Nikawa, T. Osteoactivin fragments produced by ectodomain shedding induce MMP-3 expression via ERK pathway in mouse NIH-3T3 fibroblasts. FEBS Lett., 2007, 581(30), 5743-5750.
145. Chung, J.S.; Sato, K.; Dougherty, I.I.; Cruz, P.D. Jr.; Ariizumi, K. DC-HIL is a negative regulator of T lymphocyre activation. Blood, 2007, 109(10), 4320-4327.
146. Yardley, D.A.; Weaver, R.; Melisko, M.; Saleh, M.N.; Arena, F.P.; Forero, A.; Cigler, T.; Stopeck, A.; Citron, D.; Oliff, I.; Bechhold, R.; Loutfi, R.; Garcia, A.; Crowley, E.; Green, J.; Yellin, M.J.; Davis, T.A.; Vahdat, L.T. A randomized phase 2 study of the antibody-drug cconjugate CDX-011 in advanced GPNMBoverexpressing breast cancer. The EMERGE study. Cancer Res. 2012, 72(24s3), P6-10-01.
147. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer, 2012, 12, 252-264.
148. Linsley, P.S.; Clark, E.A.; Ledbetter, J.A. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc. Natl. Acad. Sci. USA, 1990, 87, 5031-5035.
149. Schneider, H.; Mandelbrot, D.A.; Greenwald, R.J.; Ng, F.; Lechler, R.; Sharpe, A.H.; Rudd, C.E. Cutting edge: CTLA-4 (CD152) differentially regulates mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) in CD4+ T cells from receptor/ligand-deficient mice. J. Immunol., 2002, 3475-3479.
150. Schwartz, R.H. Co-stimulation of T lymphocytes: The role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell, 1992, 71, 1065-1068.
151. Qureshi, O.S.; Zheng, Y.; Nakamura, K.; Attridge, K.; Manzotti, C.; Schmidt, E.M.; Baker, J.; Jeffery, L.E.; Kaur, S.; Briggs, Z.; Hou, T.Z.; Futter, C.E.; Anderson, G.; Walker, L.S.; Sansom, D.M. Trans-endocytosis of CD80 and CD86: A molecular basis for the cell-extrinsic function of CTLA-4. Science, 2011, 332(6029), 600-603.
152. Lenschow, D.J.; Walunas, T.L; Bluestone, J.A. CD28/B7 system of T cell co-stimulation. Annu. Rev. Immunol., 1996, 14, 233-258.
153. Rudd, C.E.; Taylor, A.; Schneider, H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol. Rev., 2009, 229, 12-26.
154. Ribas, A. Clinical development of the anti-CTLA-4 antibody tremelimumab. Semin. Oncol., 2010, 37, 450-454.
155. Huxley, P.; Sutton, D.H.; Debnam, P.; Matthews, I.R.; Brewer, J.E.; Rose, J.; Trickett, M.; Williams, D.D.; Andersen, T.B.; Classon, B.J. High-affinity small molecule inhibitors of T cell costimulation: Compounds for immunotherapy. Chem. Biol., 2004, 11, 1651-1658.
156. Erbe, D.V.; Wang, S.; Xing, Y.; Tobin, J.F. Small molecule ligands define a binding site on the immune regulatory protein B7.1. J. Biol. Chem., 2002, 277, 7363-7368.
157. Larsson, M.; Shankar, E.M.; Che, K.F.; Saeidi, A.; Ellegard, R.; Barathan, M.; Velu, V.; Kamarulzaman, A. Molecular signatures of T-cell inhibition in HIV-1 infection. Retrovirol., 2013, 10, 31.
158. Freeman, G.J. Structures of PD-1 with its ligands: Sideways and dancing cheek to cheek. Proc. Natl. Acad. Sci. USA, 2008, 105 (30), 10275-10276.
159. Chen, D.S.; Irving, B.A.; Hodi, S.F. Molecular pathways: Next generation immunotherapy: Inhibiting programmed death-ligand 1 and programmed death-1. Clin. Cancer Res., 2012, 18(24), 6580-6587.
160. Dong, H.; Strome, S.E.; Salomao, D.R.; Tamura, H.; Hirano, F.; Flies D.B.; Roche, P.C.; Lu, J.; Zhu, G.; Tamada, K.; Lennon, V.A.; Celis, E.; Chen, L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med., 2002, 8, 793-800.
161. Chen, L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat. Rev. Immunol., 2004, 4, 336-347.
162. Flies, D.B.; Sandler, B.J.; Sznol, M.; Chen, L. Blockade of the B7-H1/PD-1 pathway for cancer immunotherapy. Yale J. Biol. Med., 2011, 84, 409-421.
163. Shi, L.; Chen, S.; Yang, L.; Li, Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J. Hematol. Oncol., 2013, 6, 74.
164. Parsa, A.T.; Waldron, J.S.; Panner, A.; Crane, C.A.; Parney, I.F.; Barry, J.J.; Cachola, K.E.; Murray, J.C.; Tihan, T.; Jensen, M.C.; Mischel, P.S.; Stokoe, D.; Pieper, R.O. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med., 2007, 13, 84-88.
165. Marzec, M.; Zhang, Q.; Goradia, A.; Raghunath, P.N.; Liu, X.; Paessler, M.; Wang, H.Y.; Wysocka, M.; Cheng, M.; Ruggeri, B.A.; Wasik, M.A. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive proteinCD274 (PD-L1, B7-H1). Proc. Natl. Acad. Sci. USA 2008, 105, 20852-20857.
166. Marzec, M.; Zhang, Q.; Goradia, A.; Raghunath, P.N.; Liu, X.; Paessler, M.; Wang, H.Y.; Wysocka, M.; Cheng, M.; Ruggeri, B.A.; Wasik, M.A. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive proteinCD274 (PD-L1, B7-H1). Proc. Natl. Acad. Sci. USA, 2008, 105, 20852-20857.
167. Jadus, M.R.; Natividad, J.; Mai, A.; Ouyang, Y.; Lambrecht, N.; Szabo, S.; Ge, L.; Hoa, N.; Dacosta-Iyer, M.G. Lung cancer: A classic example of tumor escape and progression while providing opportunities for immunological intervention. Clin. Dev. Immunol., 2012, 2012, 160724.
168. Sharpe, A.H.; Butte, M.J.; Oyama, S. Modulators of immunoinhibitory receptor PD-1, and methods of use thereof. PCT Patent WO 2011/082400, July 7, 2011.
169. Differding Consulting. Available at: http://www.differding.com/ data/AUNP_12_A_novel_peptide_therapeutic_targeting_PD_1_im mune_checkpoint_pathway_for_cancer_immunotherapy.pdf (Accessed 21 November 2014).
170. Sasikumar, P.G.N.; Ramachandra, M.; Vadlamani, S.K.; Vemula, K.R.; Satyam, L.K.; Subbarao, K.; Shrimali, K.R.; Kandepudu, S. Immunosuppression modulating compounds. US Patent US 2011/0318373, 29, December 29, 2011.
171. Sasikumar, P.G.; Satyam, L.K.; Shrimali, R.K.; Subbarao, K.; Ramachandra, R.; Vadlamani, S.; Reddy, A.; Kumar, A.; Srinivas, A.; Reddy, S.; Gopinath, S.; Samiulla, D.S.; Ramachandra, M. Demonstration of anti-tumor efficacy in multiple preclinical cancer models using a novel peptide inhibitor (Aurigene-012) of the PD1 signaling pathway. Cancer Res., 2012,72(8), Suppl.1, Abstract 2850.
172. Sasikumar, P.G.N.; Ramachandra, M. Immunomodulating cyclic compounds from the BC loop of human PD1. PCT Patent WO 2013/144704, October 3, 2013.
173. Del Rio, M.L.; Lucas, C.L.; Buhler, L.; Rayat, G.; Rodriguez-Barbosa, J.I. Hvem/light/btla/cd160 cosignaling pathways as targets for immune regulation. J. Leukoc. Biol., 2010, 87, 223-235.
174. Murphy, K.P; Watanabe, N.; Murphy, T.L.; Yang, J. BTLA Nucleic Acids. US Patent US 7304149 B2, December 4, 2007.
175. Pedersen, C. The B7-H3 protein and its role in breast cancer treatment response. Master's Thesis, Norwegian University of Science and Technology: Trondheim, May 2012.
176. Greenwald, R.J.; Freeman, G.J.; Sharpe, A.H. The B7 family revisited. Annu. Rev. Immunol., 2005, 23, 515-548.
177. Carreno, B.M.; Collins, M. The B7 family of ligands and its receptors: New pathways for co-stimulation and inhibition of immune responses. Annu. Rev. Immunol., 2002, 20, 29-53.
178. Yi, K.H.; Chen, L. Fine tuning the immune response through B7-H3 and B7-H4. Immunol. Rev., 2009, 229(1), 145-151.
179. Loos, M.; Hedderich, D.M.; Friess, H.; Kleeff, J. B7-H3 and its role in antitumor immunity. 2010, 1-7.
180. Chen, Y.W.; Tekle, C.; Fostad, O. The immunoregulatory protein human B7H3 is a tumor-associated antigen that regulates tumor cell migration and invasion. Curr. Cancer Drug Targ., 2008, 8(5), 404-413.
181. Liu, H.; Tekle, C.; Chen, Y.W.; Kristian, A.; Zhao, Y.; Zhao, M.; Liu, Z.; Ding, Y.; Wang, B.; Maelandsmo, G.M.; Nesland, J.M.; Fodstad, O.; Tan, M. B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation. Mol. Cancer Ther., 2011, 10 (6), 960-971.
182. Choi, I.H.; Zhu, G.; Sica, G. L.; Strome, S.E.; Cheville, J.C.; Lau, J.S.; Zhu, Y.; Flies, D.B.; Tamada, K.; Chen, L. Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. J. Immunol. 2003, 171, 4650-4654.
183. Kryczek, I.; Zou, L.; Rodriguez, P.; Zhu, G.; Wei, S.; Mottram, P.; Brumlik, M.; Cheng, P.; Curiel, T.; Myers, L.; Lackner, A.; Alvarez, X.; Ochoa, A.; Chen, L.; Zou, W. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med., 2006, 203, 871-881.
184. Krambeck, A.E.; Thompson, R.H.; Dong, H.; Lohse, C.M.; Park, E.S.; Kuntz, S.M.; Leibovich, B.C.; Blute, M.L.; Cheville, J.C.; Kwon, E.D. Sed B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival. Proc. Natl. Acad. Sci. USA, 2006, 103, 10391-10396.
185. Sedy, J.R.; Gavrieli, M.; Potter, K.G.; Hurchla, M.A.; Lindsley, R.C.; Hildner, K.; Scheu, S.; Pfeffer, K.; Ware, C.F.; Murphy, T.L.; Murphy, K.M. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat. Immunol., 2005, 6, 90-98.
186. Sica, G.L.; Choi, I.H.; Zhu, G.; Tamada, K.; Wang, S.D.; Tamura, H.; Chapoval, A.I.; Flies, D.B.; Bajorath, J.; Chen, L. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity, 2003, 18, 849-861.
187. Sierro, S.; Romero, P.; Speiser, D.E. The CD4-like molecule, LAG-3, biology and therapeutic applications. Exp. opin. Ther. Targ., 2011, 15(1), 91-101.
188. Li, N.; Wang, Y.; Forbes, K.; Vignali, K.M.; Heale, B.S.; Saftig, P.; Hartmann, D.; Black, R.A.; Rossi, J.J.; Blobel, C.P.; Dempsey, P.J.; Workman, C.J.; Vignali, D.A. Metalloproteases regulate Tcell proliferation and effector function via LAG-3. EMBO J., 2007, 26, 494-504.
189. Andreae, S.; Piras, F.; Burdin, N.; Triebel, F. Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223). J. Immunol., 2002, 168, 3874-3880.
190. Hannier, S.; Tournier, M.; Bismuth, G.; Triebel, F. CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling. J. Immunol., 1998, 161, 4058-4065.
191. Huard, B.; Tournier, M.; Hercend, T; Triebel, F.; Faure, F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur. J. Immunol., 1994, 24, 3216-3221.
192. Macon-Lemaitre, L.; Triebel, F. The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunol., 2005, 115, 170-178.
193. Woo, S.; Turnis, M.E.; Goldberg, M.V; Bankoti, J.; Selby, M.; Nirschi, C.J.; Bettini, M.L.; Gravano, D.; Vogel, P.; Liu, C.L.; Tangsombatvisit, S.; Grosso, J.F.; Netto, G.; Smeltzer, M.P.; Chaux, A.; Utz, P.J.; Workman, C.J.; Pardoll, D.M.; Korman, A.J.; Drake, C.G.; Vignali, D.A.A. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Res., 2012, 72 (4), 917-927.
194. Anderson, A.C. Tim-3: An emerging target in the cancer immunotherapy landscape. Cancer Immunol. Res., 2014, 2, 393-398.
195. Monney, L.; Sabatos, C.A.; Gaglia, J.L.; Ryu, A.; Waldner, H.; Chernova, T.; Manning, S.; Greenfield, E.A.; Coyle, A.J.; Sobel, R.A.; Freeman, G.J.; Kuchroo, V.K. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature, 2002, 415, 536-541.
196. Yang, Z.Z.; Grote, D.M.; Ziesmer, S.C.; Niki, T.; Hirashima, M.; Novak, A.J.; Witzig, T.E.; Ansell, S.M. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J. Clin. Invest., 2012, 122, 1271-1282.
197. Ngiow, S.F.; Von Scheidt, B.; Akiba, H.; Yagita, H.; Teng, M.W.; Smyth, M.J. Anti-TIM3 antibody promotes T cell IFN-[gamma]-mediated antitumor immunity and suppresses established tumors. Cancer Res., 2011, 71, 3540-3551.
198. Rangachari, M.; Zhu, C.; Sakuishi, K.; Xiao, S.; Karman, J.; Chen, A.; Angin, M.; Wakeham, A.; Greenfield, E.A.; Sobel, R.A.; Okada, H.; McKinnon, P.J.; Mak, T.W.; Addo, M.M.; Anderson, A.C.; Kuchroo, V.K. Bat3 protects T cell responses by repressing Tim-3-mediated exhaustion and death. Nat. Med., 2012, 18, 1394-1400.
199. Sakuishi, K.; Ngiow, S.F.; Sullivan, J.M.; Teng, M.W.L.; Kuchroo, V.K.; Smyth, M.J.; Anderson, A.C. TIM3+ FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology, 2013, 2, e23849.
200. Chiba, S.; Baghdadi, M; Akiba, H.; Yoshiyama, H.; Kinoshita, I.; Dosaka-Akita, H.; Fujioka, Y.; Ohba, Y.; Gorman, J.V.; Colgan, J.D.; Hirashima, M.; Uede, T.; Takaoka, A.; Yagita, H.; Jinushi, M. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol., 2012, 13, 832-842.
201. Kuchroo, V.K.; Monney, L.; Gaglia, J.L.; Greenfield, E.A.; Freeman, G.J.; Waldner, H. Compositions and methods related to TIM-3, a TH1-specific cell surface molecule. US Patent US 8101176, January 24, 2012.
202. Blumberg, R.S.; Kuchroo, V.K.; Huang, Y.; Zhu, C.; Anderson, A.C. Modulation of the immune response. PCT Patent WO 2014022332 A1, February 6, 2014.
203. Anderson, D.E.; Anderson, A.C.; Kuchroo, V.K.; Hafler, D.A. Therapeutic uses of TIM-3 modulators. US Patent US 2010/ 0061992 A1, March 11, 2010.