Adjunct strategies for tuberculosis vaccines: Modulating key immune cell regulatory mechanisms to potentiate vaccination

Frontiers in Immunology

Volumn 7, Issue DEC, 2016, Pages

  Jayashankar, Lakshmi ^a   Hafner, Richard ^a  

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

Immuno oncology; Immunometabolism; Tuberculosis; Vaccines

Indexed keywords

ADENOSINE DERIVATIVE; BCG VACCINE; GLYCOGEN SYNTHASE KINASE 3BETA; PROGRAMMED DEATH 1 RECEPTOR; RAPAMYCIN; SIRTUIN; SONIC HEDGEHOG PROTEIN; WNT PROTEIN;

ADAPTIVE IMMUNITY; AUTOPHAGY; CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; DISEASE COURSE; HUMAN; IMMUNOMETABOLISM; IMMUNOMODULATION; IMMUNOREGULATION; METABOLISM; MOUSE; MYCOBACTERIUM TUBERCULOSIS; MYELOID DERIVED SUPPRESSOR CELL; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION; SUPPRESSOR CELL; TUBERCULOSIS;

EID: 85009385398     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2016.00577     Document Type: Review

References (200)

1. Glaziou P, Floyd K, Weil D, Raviglione M. TB deaths rank alongside HIV deaths as top infectious killer. Int J Tuberc Lung Dis (2016) 20(2):143-4. doi:10.5588/ijtld.15.0985
2. da Silva MV, Massaro VJ Jr, Machado JR, Silva DA, Castellano LR, Alexandre PB, et al. Expression pattern of transcription factors and intracellular cytokines reveals that clinically cured tuberculosis is accompanied by an increase in Mycobacterium-specific Th1, Th2, and Th17 cells. Biomed Res Int (2015) 2015:591237. doi:10.1155/2015/591237
3. Singh VK, Srivastava R, Srivastava BS. Manipulation of BCG vaccine: a double-edged sword. Eur J Clin Microbiol Infect Dis (2016) 35(4):535-43. doi:10.1007/s10096-016-2579-y
4. Liu J, Tran V, Leung AS, Alexander DC, Zhu B. BCG vaccines: their mechanisms of attenuation and impact on safety and protective efficacy. Hum Vaccin (2009) 5(2):70-8. doi:10.4161/hv.5.2.7210
5. Rodrigues LC, Mangtani P, Abubakar I. How does the level of BCG vaccine protection against tuberculosis fall over time? BMJ (2011) 343:d5974. doi:10.1136/bmj.d5974
6. Andersen P, Doherty TM. The success and failure of BCG-implications for a novel tuberculosis vaccine. Nat Rev Microbiol (2005) 3(8):656-62. doi:10.1038/nrmicro1211
7. Li M, Liu H, Zhao X, Wan K. Comparative analysis of human B cell epitopes based on BCG genomes. Biomed Res Int (2016) 2016:3620141. doi:10.1155/2016/3620141
8. Xin Q, Niu H, Li Z, Zhang G, Hu L, Wang B, et al. Subunit vaccine consisting of multi-stage antigens has high protective efficacy against Mycobacterium tuberculosis infection in mice. PLoS One (2013) 8(8):e72745. doi:10.1371/journal.pone.0072745
9. Cardona PJ, Amat I, Gordillo S, Arcos V, Guirado E, Diaz J, et al. Immunotherapy with fragmented Mycobacterium tuberculosis cells increases the effectiveness of chemotherapy against a chronical infection in a murine model of tuberculosis. Vaccine (2005) 23(11):1393-8. doi:10.1016/j.vaccine.2004.09.008
10. von Reyn CF, Mtei L, Arbeit RD, Waddell R, Cole B, Mackenzie T, et al. Prevention of tuberculosis in Bacille Calmette-Guerin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine. AIDS (2010) 24(5):675-85. doi:10.1097/QAD.0b013e3283350f1b
11. Sweeney KA, Dao DN, Goldberg MF, Hsu T, Venkataswamy MM, Henao-Tamayo M, et al. A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis. Nat Med (2011) 17(10):1261-8. doi:10.1038/nm.2420
12. Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet (2013) 381(9871):1021-8. doi:10.1016/S0140-6736(13)60177-4
13. Ndiaye BP, Thienemann F, Ota M, Landry BS, Camara M, Dieye S, et al. Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial. Lancet Respir Med (2015) 3(3):190-200. doi:10.1016/S2213-2600(15)00037-5
14. Geldenhuys H, Mearns H, Miles DJ, Tameris M, Hokey D, Shi Z, et al. The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: a randomized controlled trial. Vaccine (2015) 33(30):3592-9. doi:10.1016/j.vaccine.2015.05.036
15. Luabeya AK, Kagina BM, Tameris MD, Geldenhuys H, Hoff ST, Shi Z, et al. First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults. Vaccine (2015) 33(33):4130-40. doi:10.1016/j.vaccine.2015.06.051
16. Penn-Nicholson A, Geldenhuys H, Burny W, van der Most R, Day CL, Jongert E, et al. Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting. Vaccine (2015) 33(32):4025-34. doi:10.1016/j.vaccine.2015.05.088
17. Abubakar I, Lipman M, McHugh TD, Fletcher H. Uniting to end the TB epidemic: advances in disease control from prevention to better diagnosis and treatment. BMC Med (2016) 14:47. doi:10.1186/s12916-016-0599-1
18. Orme IM, Robinson RT, Cooper AM. The balance between protective and pathogenic immune responses in the TB-infected lung. Nat Immunol (2015) 16(1):57-63. doi:10.1038/ni.3048
19. Kiran D, Podell BK, Chambers M, Basaraba RJ. Host-directed therapy targeting the Mycobacterium tuberculosis granuloma: a review. Semin Immunopathol (2016) 38(2):167-83. doi:10.1007/s00281-015-0537-x
20. Hotchkiss RS, Moldawer LL. Parallels between cancer and infectious disease. N Engl J Med (2014) 371(4):380-3. doi:10.1056/NEJMcibr1404664
21. Mahon RN, Hafner R. Immune cell regulatory pathways unexplored as host-directed therapeutic targets for Mycobacterium tuberculosis: an opportunity to apply precision medicine innovations to infectious diseases. Clin Infect Dis (2015) 61(Suppl 3):S200-16. doi:10.1093/cid/civ621
22. Qualls JE, Murray PJ. Immunometabolism within the tuberculosis granuloma: amino acids, hypoxia, and cellular respiration. Semin Immunopathol (2015) 38(2):139-52. doi:10.1007/s00281-015-0534-0
23. Dallenga T, Schaible UE. Neutrophils in tuberculosis-first line of defence or booster of disease and targets for host-directed therapy? Pathog Dis (2016) 74(3):pii: ftw012. doi:10.1093/femspd/ftw012
24. Kolahian S, Oz HH, Zhou B, Griessinger CM, Rieber N, Hartl D. The emerging role of myeloid-derived suppressor cells in lung diseases. Eur Respir J (2016) 47(3):967-77. doi:10.1183/13993003.01572-2015
25. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature (2004) 432(7020):1032-6. doi:10.1038/nature03029
26. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell (2011) 147(4):728-41. doi:10.1016/j.cell.2011.10.026
27. Yuk JM, Jo EK. Host immune responses to mycobacterial antigens and their implications for the development of a vaccine to control tuberculosis. Clin Exp Vaccine Res (2014) 3(2):155-67. doi:10.7774/cevr.2014.3.2.155
28. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell (2004) 119(6):753-66. doi:10.1016/j.cell.2004.11.038
29. Vergne I, Singh S, Roberts E, Kyei G, Master S, Harris J, et al. Autophagy in immune defense against Mycobacterium tuberculosis. Autophagy (2006) 2(3):175-8. doi:10.4161/auto.2830
30. Alonso S, Pethe K, Russell DG, Purdy GE. Lysosomal killing of Mycobacterium mediated by ubiquitin-derived peptides is enhanced by autophagy. Proc Natl Acad Sci U S A (2007) 104(14):6031-6. doi:10.1073/pnas.0700036104
31. Jo EK, Shin DM, Choi AM. Autophagy: cellular defense to excessive inflammation. Microbes Infect (2012) 14(2):119-25. doi:10.1016/j.micinf.2011.08.014
32. Jo EK, Yuk JM, Shin DM, Sasakawa C. Roles of autophagy in elimination of intracellular bacterial pathogens. Front Immunol (2013) 4:97. doi:10.3389/fimmu.2013.00097
33. Meerak J, Wanichwecharungruang SP, Palaga T. Enhancement of immune response to a DNA vaccine against Mycobacterium tuberculosis Ag85B by incorporation of an autophagy inducing system. Vaccine (2013) 31(5):784-90. doi:10.1016/j.vaccine.2012.11.075
34. Bento CF, Empadinhas N, Mendes V. Autophagy in the fight against tuberculosis. DNA Cell Biol (2015) 34(4):228-42. doi:10.1089/dna.2014.2745
35. Rubinsztein DC, Bento CF, Deretic V. Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J Exp Med (2015) 212(7):979-90. doi:10.1084/jem.20150956
36. Ghadimi D, de Vrese M, Heller KJ, Schrezenmeir J. Lactic acid bacteria enhance autophagic ability of mononuclear phagocytes by increasing Th1 autophagy-promoting cytokine (IFN-gamma) and nitric oxide (NO) levels and reducing Th2 autophagy-restraining cytokines (IL-4 and IL-13) in response to Mycobacterium tuberculosis antigen. Int Immunopharmacol (2010) 10(6):694-706. doi:10.1016/j.intimp.2010.03.014
37. Shaler CR, Horvath C, Lai R, Xing Z. Understanding delayed T-cell priming, lung recruitment, and airway luminal T-cell responses in host defense against pulmonary tuberculosis. Clin Dev Immunol (2012) 2012:628293. doi:10.1155/2012/628293
38. Netea-Maier RT, Plantinga TS, Van De Veerdonk FL, Smit JW, Netea MG. Modulation of inflammation by autophagy: consequences for human disease. Autophagy (2015) 12(2):245-60. doi:10.1080/15548627.2015.1071759
39. Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL Jr, Eissa NT. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med (2009) 15(3):267-76. doi:10.1038/nm.1928
40. Ni Cheallaigh C, Keane J, Lavelle EC, Hope JC, Harris J. Autophagy in the immune response to tuberculosis: clinical perspectives. Clin Exp Immunol (2011) 164(3):291-300. doi:10.1111/j.1365-2249.2011.04381.x
41. Tey SK, Khanna R. Host immune system strikes back: autophagy-mediated antigen presentation bypasses viral blockade of the classic MHC class I processing pathway. Autophagy (2012) 8(12):1839-41. doi:10.4161/auto.21860
42. Sarkar S. Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans (2013) 41(5):1103-30. doi:10.1042/BST20130134
43. Jagannath C, Bakhru P. Rapamycin-induced enhancement of vaccine efficacy in mice. Methods Mol Biol (2012) 821:295-303. doi:10.1007/978-1-61779-430-8_18
44. Gupta A, Pant G, Mitra K, Madan J, Chourasia MK, Misra A. Inhalable particles containing rapamycin for induction of autophagy in macrophages infected with Mycobacterium tuberculosis. Mol Pharm (2014) 11(4):1201-7. doi:10.1021/mp4006563
45. Hu D, Wu J, Zhang R, Chen L, Chen Z, Wang X, et al. Autophagy-targeted vaccine of LC3-LpqH DNA and its protective immunity in a murine model of tuberculosis. Vaccine (2014) 32(20):2308-14. doi:10.1016/j.vaccine.2014.02.069
46. Schiebler M, Brown K, Hegyi K, Newton SM, Renna M, Hepburn L, et al. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. EMBO Mol Med (2015) 7(2):127-39. doi:10.15252/emmm.201404137
47. Napier RJ, Rafi W, Cheruvu M, Powell KR, Zaunbrecher MA, Bornmann W, et al. Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis. Cell Host Microbe (2011) 10(5):475-85. doi:10.1016/j.chom.2011.09.010
48. Bruns H, Stegelmann F, Fabri M, Dohner K, van Zandbergen G, Wagner M, et al. Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages. J Immunol (2012) 189(8):4069-78. doi:10.4049/jimmunol.1201538
49. Steiger J, Stephan A, Inkeles MS, Realegeno S, Bruns H, Kroll P, et al. Imatinib triggers phagolysosome acidification and antimicrobial activity against Mycobacterium bovis Bacille Calmette-Guerin in glucocorticoid-treated human macrophages. J Immunol (2016) 197(1):222-32. doi:10.4049/jimmunol.1502407
50. Parihar SP, Guler R, Khutlang R, Lang DM, Hurdayal R, Mhlanga MM, et al. Statin therapy reduces the Mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation. J Infect Dis (2014) 209(5):754-63. doi:10.1093/infdis/jit550
51. Skerry C, Pinn ML, Bruiners N, Pine R, Gennaro ML, Karakousis PC. Simvastatin increases the in vivo activity of the first-line tuberculosis regimen. J Antimicrob Chemother (2014) 69(9):2453-7. doi:10.1093/jac/dku166
52. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol (2001) 2(3):261-8. doi:10.1038/85330
53. Yao S, Chen L. PD-1 as an immune modulatory receptor. Cancer J (2014) 20(4):262-4. doi:10.1097/PPO.0000000000000060
54. Jurado JO I, Alvarez B, Pasquinelli V, Martinez GJ, Quiroga MF, Abbate E, et al. Programmed death (PD)-1:PD-ligand 1/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis. J Immunol (2008) 181(1):116-25. doi:10.4049/jimmunol.181.1.116
55. Alvarez IB, Pasquinelli V, Jurado JO, Abbate E, Musella RM, de la Barrera SS, et al. Role played by the programmed death-1-programmed death ligand pathway during innate immunity against Mycobacterium tuberculosis. J Infect Dis (2010) 202(4):524-32. doi:10.1086/654932
56. Wherry EJ. T cell exhaustion. Nat Immunol (2011) 12(6):492-9. doi:10.1038/ni.2035
57. Periasamy S, Dhiman R, Barnes PF, Paidipally P, Tvinnereim A, Bandaru A, et al. Programmed death 1 and cytokine inducible SH2-containing protein dependent expansion of regulatory T cells upon stimulation with Mycobacterium tuberculosis. J Infect Dis (2011) 203(9):1256-63. doi:10.1093/infdis/jir011
58. Hassan SS, Akram M, King EC, Dockrell HM, Cliff JM. PD-1, PD-L1 and PD-L2 gene expression on T-cells and natural killer cells declines in conjunction with a reduction in PD-1 protein during the intensive phase of tuberculosis treatment. PLoS One (2015) 10(9):e0137646. doi:10.1371/journal.pone.0137646
59. Pollock KM, Montamat-Sicotte DJ, Grass L, Cooke GS, Kapembwa MS, Kon OM, et al. PD-1 expression and cytokine secretion profiles of Mycobacterium tuberculosis-specific CD4+ T-cell subsets; potential correlates of containment in HIV-TB co-infection. PLoS One (2016) 11(1):e0146905. doi:10.1371/journal.pone.0146905
60. Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther (2015) 37(4):764-82. doi:10.1016/j.clinthera.2015.02.018
61. Morse MA, Lyerly HK. Checkpoint blockade in combination with cancer vaccines. Vaccine (2015) 33(51):7377-85. doi:10.1016/j.vaccine.2015.10.057
62. Fu J I, Malm J, Kadayakkara DK, Levitsky H, Pardoll D, Kim YJ. Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors. Cancer Res (2014) 74(15):4042-52. doi:10.1158/0008-5472.CAN-13-2685
63. Lazar-Molnar E, Chen B, Sweeney KA, Wang EJ, Liu W, Lin J, et al. Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci U S A (2010) 107(30):13402-7. doi:10.1073/pnas.1007394107
64. Attanasio J, Wherry EJ. Costimulatory and coinhibitory receptor pathways in infectious disease. Immunity (2016) 44(5):1052-68. doi:10.1016/j.immuni.2016.04.022
65. Hafalla JC, Claser C, Couper KN, Grau GE, Renia L, de Souza JB, et al. The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to plasmodium-induced acute immune pathology. PLoS Pathog (2012) 8(2):e1002504. doi:10.1371/journal.ppat.1002504
66. Karunarathne DS, Horne-Debets JM, Huang JX, Faleiro R, Leow CY, Amante F, et al. Programmed death-1 ligand 2-mediated regulation of the PD-L1 to PD-1 axis is essential for establishing CD4(+) T cell immunity. Immunity (2016) 45(2):333-45. doi:10.1016/j.immuni.2016.07.017
67. Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity (2016) 45(2):358-73. doi:10.1016/j.immuni.2016.07.008
68. Martinez GJ, Pereira RM, Aijo T, Kim EY, Marangoni F, Pipkin ME, et al. The transcription factor NFAT promotes exhaustion of activated CD8(+) T cells. Immunity (2015) 42(2):265-78. doi:10.1016/j.immuni.2015.01.006
69. Shou J, Jing J, Xie J, You L, Jing Z, Yao J, et al. Nuclear factor of activated T cells in cancer development and treatment. Cancer Lett (2015) 361(2):174-84. doi:10.1016/j.canlet.2015.03.005
70. Linch SN, McNamara MJ, Redmond WL. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol (2015) 5:34. doi:10.3389/fonc.2015.00034
71. Snelgrove RJ, Cornere MM, Edwards L, Dagg B, Keeble J, Rodgers A, et al. OX40 ligand fusion protein delivered simultaneously with the BCG vaccine provides superior protection against murine Mycobacterium tuberculosis infection. J Infect Dis (2012) 205(6):975-83. doi:10.1093/infdis/jir868
72. Sanmamed MF, Pastor F, Rodriguez A, Perez-Gracia JL, Rodriguez-Ruiz ME, Jure-Kunkel M, et al. Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol (2015) 42(4):640-55. doi:10.1053/j.seminoncol.2015.05.014
73. Zaunders JJ, Munier ML, Seddiki N, Pett S, Ip S, Bailey M, et al. High levels of human antigen-specific CD4+ T cells in peripheral blood revealed by stimulated coexpression of CD25 and CD134 (OX40). J Immunol (2009) 183(4):2827-36. doi:10.4049/jimmunol.0803548
74. Ruby CE, Montler R, Zheng R, Shu S, Weinberg AD. IL-12 is required for anti-OX40-mediated CD4 T cell survival. J Immunol (2008) 180(4):2140-8. doi:10.4049/jimmunol.180.4.2140
75. Guo Z, Wang X, Cheng D, Xia Z, Luan M, Zhang S. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One (2014) 9(2):e89350. doi:10.1371/journal.pone.0089350
76. Zubairi S, Sanos SL, Hill S, Kaye PM. Immunotherapy with OX40L-Fc or anti-CTLA-4 enhances local tissue responses and killing of Leishmania donovani. Eur J Immunol (2004) 34(5):1433-40. doi:10.1002/eji.200324021
77. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol (2004) 22:531-62. doi:10.1146/annurev.immunol.21.120601.141122
78. Henao-Tamayo MI, Obregon-Henao A, Arnett K, Shanley CA, Podell B, Orme IM, et al. Effect of Bacillus Calmette-Guerin vaccination on CD4+Foxp3+ T cells during acquired immune response to Mycobacterium tuberculosis infection. J Leukoc Biol (2015) 99(4):605-17. doi:10.1189/jlb.4A0614-308RR
79. Luo Y, Ma X, Liu X, Lu X, Niu H, Yu H, et al. IL-28B down-regulates regulatory T cells but does not improve the protective immunity following tuberculosis subunit vaccine immunization. Int Immunol (2015) 28(2):77-85. doi:10.1093/intimm/dxv061
80. Wergeland I, Assmus J, Dyrhol-Riise AM. T regulatory cells and immune activation in Mycobacterium tuberculosis infection and the effect of preventive therapy. Scand J Immunol (2011) 73(3):234-42. doi:10.1111/j.1365-3083.2010.02496.x
81. Lieske NV, Tonby K, Kvale D, Dyrhol-Riise AM, Tasken K. Targeting tuberculosis and HIV infection-specific regulatory T cells with MEK/ERK signaling pathway inhibitors. PLoS One (2015) 10(11):e0141903. doi:10.1371/journal.pone.0141903
82. O'Garra A, Vieira P. Regulatory T cells and mechanisms of immune system control. Nat Med (2004) 10(8):801-5. doi:10.1038/nm0804-801
83. Joosten SA, Ottenhoff TH. Human CD4 and CD8 regulatory T cells in infectious diseases and vaccination. Hum Immunol (2008) 69(11):760-70. doi:10.1016/j.humimm.2008.07.017
84. Cooper AM. Cell-mediated immune responses in tuberculosis. Annu Rev Immunol (2009) 27:393-422. doi:10.1146/annurev.immunol.021908.132703
85. Marin ND, Paris SC, Velez VM, Rojas CA, Rojas M, Garcia LF. Regulatory T cell frequency and modulation of IFN-gamma and IL-17 in active and latent tuberculosis. Tuberculosis (Edinb) (2010) 90(4):252-61. doi:10.1016/j.tube.2010.05.003
86. Feruglio SL, Tonby K, Kvale D, Dyrhol-Riise AM. Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of active Mycobacterium tuberculosis infection. Clin Exp Immunol (2015) 179(3):454-65. doi:10.1111/cei.12468
87. Shafiani S, Tucker-Heard G, Kariyone A, Takatsu K, Urdahl KB. Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis. J Exp Med (2010) 207(7):1409-20. doi:10.1084/jem.20091885
88. Kumar NP, Moideen K, Banurekha VV, Nair D, Sridhar R, Nutman TB, et al. IL-27 and TGFbeta mediated expansion of Th1 and adaptive regulatory T cells expressing IL-10 correlates with bacterial burden and disease severity in pulmonary tuberculosis. Immun Inflamm Dis (2015) 3(3):289-99. doi:10.1002/iid3.68
89. He XY, Xiao L, Chen HB, Hao J, Li J, Wang YJ, et al. T regulatory cells and Th1/Th2 cytokines in peripheral blood from tuberculosis patients. Eur J Clin Microbiol Infect Dis (2010) 29(6):643-50. doi:10.1007/s10096-010-0908-0
90. Jackson-Sillah D, Cliff JM, Mensah GI, Dickson E, Sowah S, Tetteh JK, et al. Recombinant ESAT-6-CFP10 fusion protein induction of Th1/Th2 cytokines and FoxP3 expressing Treg cells in pulmonary TB. PLoS One (2013) 8(6):e68121. doi:10.1371/journal.pone.0068121
91. Rossowska J, Pajtasz-Piasecka E, Anger N, Wojas-Turek J, Kicielinska J, Piasecki E, et al. Cyclophosphamide and IL-12-transduced DCs enhance the antitumor activity of tumor antigen-stimulated DCs and reduce Tregs and MDSCs number. J Immunother (2014) 37(9):427-39. doi:10.1097/CJI.0000000000000054
92. Liu G, Bi Y, Shen B, Yang H, Zhang Y, Wang X, et al. SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1alpha-dependent glycolysis. Cancer Res (2014) 74(3):727-37. doi:10.1158/0008-5472.CAN-13-2584
93. Centuori SM, Trad M, LaCasse CJ, Alizadeh D, Larmonier CB, Hanke NT, et al. Myeloid-derived suppressor cells from tumor-bearing mice impair TGF-beta-induced differentiation of CD4+CD25+FoxP3+ Tregs from CD4+CD25-FoxP3-T cells. J Leukoc Biol (2012) 92(5):987-97. doi:10.1189/jlb.0911465
94. Yang B, Wang X, Jiang J, Zhai F, Cheng X. Identification of CD244-expressing myeloid-derived suppressor cells in patients with active tuberculosis. Immunol Lett (2014) 158(1-2):66-72. doi:10.1016/j.imlet.2013.12.003
95. du Plessis N, Loebenberg L, Kriel M, von Groote-Bidlingmaier F, Ribechini E, Loxton AG, et al. Increased frequency of myeloid-derived suppressor cells during active tuberculosis and after recent Mycobacterium tuberculosis infection suppresses T-cell function. Am J Respir Crit Care Med (2013) 188(6):724-32. doi:10.1164/rccm.201302-0249OC
96. Dorhoi A, Kaufmann SH. Versatile myeloid cell subsets contribute to tuberculosis-associated inflammation. Eur J Immunol (2015) 45(8):2191-202. doi:10.1002/eji.201545493
97. Fedatto PF, Sergio CA, Paula MO, Gembre AF, Franco LH, Wowk PF, et al. Protection conferred by heterologous vaccination against tuberculosis is dependent on the ratio of CD4(+)/CD4(+) Foxp3(+) cells. Immunology (2012) 137(3):239-48. doi:10.1111/imm.12006
98. Bhattacharya D, Dwivedi VP, Kumar S, Reddy MC, Van Kaer L, Moodley P, et al. Simultaneous inhibition of T helper 2 and T regulatory cell differentiation by small molecules enhances Bacillus Calmette-Guerin vaccine efficacy against tuberculosis. J Biol Chem (2014) 289(48):33404-11. doi:10.1074/jbc.M114.600452
99. Quinn KM, Rich FJ, Goldsack LM, de Lisle GW, Buddle BM, Delahunt B, et al. Accelerating the secondary immune response by inactivating CD4(+)CD25(+) T regulatory cells prior to BCG vaccination does not enhance protection against tuberculosis. Eur J Immunol (2008) 38(3):695-705. doi:10.1002/eji.200737888
100. Huang Z, Wu Y, Zhou X, Qian J, Zhu W, Shu Y, et al. Clinical efficacy of mTOR inhibitors in solid tumors: a systematic review. Future Oncol (2015) 11(11):1687-99. doi:10.2217/fon.15.70
101. Leone RD, Lo YC, Powell JD. A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J (2015) 13:265-72. doi:10.1016/j.csbj.2015.03.008
102. Muller T. The safety of istradefylline for the treatment of Parkinson's disease. Expert Opin Drug Saf (2015) 14(5):769-75. doi:10.1517/14740338.2015.1014798
103. Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med (2006) 203(12):2691-702. doi:10.1084/jem.20061104
104. Weed DT, Vella JL, Reis IM, De la Fuente AC, Gomez C, Sargi Z, et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res (2015) 21(1):39-48. doi:10.1158/1078-0432.CCR-14-1711
105. Byersdorfer CA. The role of fatty acid oxidation in the metabolic reprograming of activated T-cells. Front Immunol (2014) 5:641. doi:10.3389/fimmu.2014.00641
106. Rodriguez PC, Ochoa AC. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev (2008) 222:180-91. doi:10.1111/j.1600-065X.2008.00608.x
107. Yang CS, Kim JJ, Lee HM, Jin HS, Lee SH, Park JH, et al. The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy. Autophagy (2014) 10(5):785-802. doi:10.4161/auto.28072
108. Kala R, Shah HN, Martin SL, Tollefsbol TO. Epigenetic-based combinatorial resveratrol and pterostilbene alters DNA damage response by affecting SIRT1 and DNMT enzyme expression, including SIRT1-dependent gamma-H2AX and telomerase regulation in triple-negative breast cancer. BMC Cancer (2015) 15:672. doi:10.1186/s12885-015-1693-z
109. Hu J, Jing H, Lin H. Sirtuin inhibitors as anticancer agents. Future Med Chem (2014) 6(8):945-66. doi:10.4155/fmc.14.44
110. Xu R, Shimizu F, Hovinga K, Beal K, Karimi S, Droms L, et al. Molecular and clinical effects of notch inhibition in glioma patients: a phase 0/I trial. Clin Cancer Res (2016) 22(19):4786-96. doi:10.1158/1078-0432.CCR-16-0048
111. Li W, Li J, Sama AE, Wang H. Carbenoxolone blocks endotoxin-induced protein kinase R (PKR) activation and high mobility group box 1 (HMGB1) release. Mol Med (2013) 19:203-11. doi:10.2119/molmed.2013.00064
112. Parker KH, Sinha P, Horn LA, Clements VK, Yang H, Li J, et al. HMGB1 enhances immune suppression by facilitating the differentiation and suppressive activity of myeloid-derived suppressor cells. Cancer Res (2014) 74(20):5723-33. doi:10.1158/0008-5472.CAN-13-2347
113. Grover A, Troudt J, Foster C, Basaraba R, Izzo A. High mobility group box 1 acts as an adjuvant for tuberculosis subunit vaccines. Immunology (2014) 142(1):111-23. doi:10.1111/imm.12236
114. Shen L, Sundstedt A, Ciesielski M, Miles KM, Celander M, Adelaiye R, et al. Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. Cancer Immunol Res (2015) 3(2):136-48. doi:10.1158/2326-6066.CIR-14-0036
115. Sternberg C, Armstrong A, Pili R, Ng S, Huddart R, Agarwal N, et al. Randomized, double-blind, placebo-controlled phase III study of tasquinimod in men with metastatic castration-resistant prostate cancer. J Clin Oncol (2016) 34(22):2636-43. doi:10.1200/JCO.2016.66.9697
116. Blumenthal A, Nagalingam G, Huch JH, Walker L, Guillemin GJ, Smythe GA, et al. M. tuberculosis induces potent activation of IDO-1, but this is not essential for the immunological control of infection. PLoS One (2012) 7(5):e37314. doi:10.1371/journal.pone.0037314
117. Mehra S, Alvarez X, Didier PJ, Doyle LA, Blanchard JL, Lackner AA, et al. Granuloma correlates of protection against tuberculosis and mechanisms of immune modulation by Mycobacterium tuberculosis. J Infect Dis (2013) 207(7):1115-27. doi:10.1093/infdis/jis778
118. Tanner R, Kakalacheva K, Miller E, Pathan AA, Chalk R, Sander CR, et al. Serum indoleamine 2, 3-dioxygenase activity is associated with reduced immunogenicity following vaccination with MVA85A. BMC Infect Dis (2014) 14:660. doi:10.1186/s12879-014-0660-7
119. Holmgaard RB, Zamarin D, Li Y, Gasmi B, Munn DH, Allison JP, et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep (2015) 13(2):412-24. doi:10.1016/j.celrep.2015.08.077
120. Bjoern J, Iversen TZ, Nitschke NJ, Andersen MH, Svane IM. Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2, 3-dioxygenase in combination with ipilimumab. Cytotherapy (2016) 18(8):1043-55. doi:10.1016/j.jcyt.2016.05.010
121. Jochems C, Fantini M, Fernando RI, Kwilas AR, Donahue RN, Lepone LM, et al. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells. Oncotarget (2016) 7(25):37762-72. doi:10.18632/oncotarget.9326
122. Blache CA, Manuel ER, Kaltcheva TI, Wong AN, Ellenhorn JD, Blazar BR, et al. Systemic delivery of Salmonella typhimurium transformed with IDO shRNA enhances intratumoral vector colonization and suppresses tumor growth. Cancer Res (2012) 72(24):6447-56. doi:10.1158/0008-5472.CAN-12-0193
123. Kao J, Ko EC, Eisenstein S, Sikora AG, Fu S, Chen SH. Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol (2011) 77(1):12-9. doi:10.1016/j.critrevonc.2010.02.004
124. Nishioka Y, Aono Y, Sone S. Role of tyrosine kinase inhibitors in tumor immunology. Immunotherapy (2011) 3(1):107-16. doi:10.2217/imt.10.79
125. Draghiciu O, Nijman HW, Hoogeboom BN, Meijerhof T, Daemen T. Sunitinib depletes myeloid-derived suppressor cells and synergizes with a cancer vaccine to enhance antigen-specific immune responses and tumor eradication. Oncoimmunology (2015) 4(3):e989764. doi:10.4161/2162402X.2014.989764
126. Lowe DB, Bose A, Taylor JL, Tawbi H, Lin Y, Kirkwood JM, et al. Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma. Oncoimmunology (2014) 3(1):e27589. doi:10.4161/onci.27589
127. Araki K, Ahmed R. AMPK: a metabolic switch for CD8+ T-cell memory. Eur J Immunol (2013) 43(4):878-81. doi:10.1002/eji.201343483
128. Singhal A, Jie L, Kumar P, Hong GS, Leow MK, Paleja B, et al. Metformin as adjunct antituberculosis therapy. Sci Transl Med (2014) 6(263):263ra159. doi:10.1126/scitranslmed.3009885
129. Ong CW, Elkington PT, Brilha S, Ugarte-Gil C, Tome-Esteban MT, Tezera LB, et al. Neutrophil-derived MMP-8 drives AMPK-dependent matrix destruction in human pulmonary tuberculosis. PLoS Pathog (2015) 11(5):e1004917. doi:10.1371/journal.ppat.1004917
130. Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vazquez G, Yurchenko E, et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity (2015) 42(1):41-54. doi:10.1016/j.immuni.2014.12.030
131. Kim JK, Yuk JM, Kim SY, Kim TS, Jin HS, Yang CS, et al. MicroRNA-125a inhibits autophagy activation and antimicrobial responses during mycobacterial infection. J Immunol (2015) 194(11):5355-65. doi:10.4049/jimmunol.1402557
132. Vashisht R, Brahmachari SK. Metformin as a potential combination therapy with existing front-line antibiotics for tuberculosis. J Transl Med (2015) 13:83. doi:10.1186/s12967-015-0443-y
133. Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A (2015) 112(6):1809-14. doi:10.1073/pnas.1417636112
134. Chen M, Zhang J, Hu F, Liu S, Zhou Z. Metformin affects the features of a human hepatocellular cell line (HepG2) by regulating macrophage polarization in a co-culture microenviroment. Diabetes Metab Res Rev (2015) 31(8):781-9. doi:10.1002/dmrr.2761
135. Ding L, Liang G, Yao Z, Zhang J, Liu R, Chen H, et al. Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget (2015) 6(34):36441-55. doi:10.18632/oncotarget.5541
136. Wang R, Green DR. Metabolic checkpoints in activated T cells. Nat Immunol (2012) 13(10):907-15. doi:10.1038/ni.2386
137. Zeng H, Chi H. mTOR signaling and transcriptional regulation in T lymphocytes. Transcription (2014) 5(2):e28263. doi:10.4161/trns.28263
138. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell (2011) 146(5):772-84. doi:10.1016/j.cell.2011.07.033
139. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol (2013) 14(11):1173-82. doi:10.1038/ni.2714
140. Kheshtchin N, Arab S, Ajami M, Mirzaei R, Ashourpour M, Mousavi N, et al. Inhibition of HIF-1alpha enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer. Cancer Immunol Immunother (2016) 65(10):1159-67. doi:10.1007/s00262-016-1879-5
141. Braverman J, Sogi KM, Benjamin D, Nomura DK, Stanley SA. HIF-1alpha is an essential mediator of IFN-gamma-dependent immunity to Mycobacterium tuberculosis. J Immunol (2016) 197(4):1287-97. doi:10.4049/jimmunol.1600266
142. Baur JA, Ungvari Z, Minor RK, Le Couteur DG, de Cabo R. Are sirtuins viable targets for improving healthspan and lifespan? Nat Rev Drug Discov (2012) 11(6):443-61. doi:10.1038/nrd3738
143. Vachharajani V, Liu T, McCall CE. Epigenetic coordination of acute systemic inflammation: potential therapeutic targets. Expert Rev Clin Immunol (2014) 10(9):1141-50. doi:10.1586/1744666X.2014.943192
144. Baharia RK, Tandon R, Sharma T, Suthar MK, Das S, Siddiqi MI, et al. Recombinant NAD-dependent SIR-2 protein of Leishmania donovani: immunobiochemical characterization as a potential vaccine against visceral leishmaniasis. PLoS Negl Trop Dis (2015) 9(3):e0003557. doi:10.1371/journal.pntd.0003557
145. Jing H, Lin H. Sirtuins in epigenetic regulation. Chem Rev (2015) 115(6):2350-75. doi:10.1021/cr500457h
146. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A (2008) 105(9):3374-9. doi:10.1073/pnas.0712145105
147. Schug TT, Xu Q, Gao H, Peres-da-Silva A, Draper DW, Fessler MB, et al. Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol (2010) 30(19):4712-21. doi:10.1128/MCB.00657-10
148. Cardoso F, Castro F, Moreira-Teixeira L, Sousa J, Torrado E, Silvestre R, et al. Myeloid sirtuin 2 expression does not impact long-term Mycobacterium tuberculosis control. PLoS One (2015) 10(7):e0131904. doi:10.1371/journal.pone.0131904
149. Chen X, Lu Y, Zhang Z, Wang J, Yang H, Liu G. Intercellular interplay between Sirt1 signalling and cell metabolism in immune cell biology. Immunology (2015) 145(4):455-67. doi:10.1111/imm.12473
150. Mellini P, Valente S, Mai A. Sirtuin modulators: an updated patent review (2012-2014). Expert Opin Ther Pat (2015) 25(1):5-15. doi:10.1517/13543776.2014.982532
151. Opal S, Ellis JL, Suri V, Freudenberg JM, Vlasuk GP, Li Y, et al. Sirt1 activation markedly alters transcription profiles and improves outcome in experimental sepsis. Shock (2016) 45(4):411-18. doi:10.1097/SHK.0000000000000528
152. Owczarczyk AB, Schaller MA, Reed M, Rasky AJ, Lombard DB, Lukacs NW. Sirtuin 1 regulates dendritic cell activation and autophagy during respiratory syncytial virus-induced immune responses. J Immunol (2015) 195(4):1637-46. doi:10.4049/jimmunol.1500326
153. Jia YY, Lu J, Huang Y, Liu G, Gao P, Wan YZ, et al. The involvement of NFAT transcriptional activity suppression in SIRT1-mediated inhibition of COX-2 expression induced by PMA/Ionomycin. PLoS One (2014) 9(5):e97999. doi:10.1371/journal.pone.0097999
154. Liu G, Bi Y, Xue L, Zhang Y, Yang H, Chen X, et al. Dendritic cell SIRT1-HIF1alpha axis programs the differentiation of CD4+ T cells through IL-12 and TGF-beta1. Proc Natl Acad Sci U S A (2015) 112(9):E957-65. doi:10.1073/pnas.1420419112
155. Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem (2006) 281(32):22429-33. doi:10.1074/jbc.R600015200
156. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis (2008) 4(2):68-75. doi:10.4161/org.4.2.5851
157. Luo T, Dunphy PS, Lina TT, McBride JW. Ehrlichia chaffeensis exploits canonical and noncanonical host Wnt signaling pathways to stimulate phagocytosis and promote intracellular survival. Infect Immun (2015) 84(3):686-700. doi:10.1128/IAI.01289-15
158. Nusse R. Cell signalling: disarming Wnt. Nature (2015) 519(7542):163-4. doi:10.1038/nature14208
159. Schaale K, Neumann J, Schneider D, Ehlers S, Reiling N. Wnt signaling in macrophages: augmenting and inhibiting mycobacteria-induced inflammatory responses. Eur J Cell Biol (2011) 90(6-7):553-9. doi:10.1016/j.ejcb.2010.11.004
160. Li Y, Shi J, Yang J, Ma Y, Cheng L, Zeng J, et al. A Wnt/beta-catenin negative feedback loop represses TLR-triggered inflammatory responses in alveolar epithelial cells. Mol Immunol (2014) 59(2):128-35. doi:10.1016/j.molimm.2014.02.002
161. Wu X, Deng G, Hao X, Li Y, Zeng J, Ma C, et al. A caspase-dependent pathway is involved in Wnt/beta-catenin signaling promoted apoptosis in Bacillus Calmette-Guerin infected RAW264.7 macrophages. Int J Mol Sci (2014) 15(3):5045-62. doi:10.3390/ijms15035045
162. Wu X, Deng G, Li M, Li Y, Ma C, Wang Y, et al. Wnt/beta-catenin signaling reduces Bacillus Calmette-Guerin-induced macrophage necrosis through a ROS-mediated PARP/AIF-dependent pathway. BMC Immunol (2015) 16:16. doi:10.1186/s12865-015-0080-5
163. Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM, Wang YC, et al. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science (2010) 329(5993):849-53. doi:10.1126/science.1188510
164. Cannon MJ, Ghosh D, Gujja S. Signaling circuits and regulation of immune suppression by ovarian tumor-associated macrophages. Vaccines (Basel) (2015) 3(2):448-66. doi:10.3390/vaccines3020448
165. Xiao YF, Yong X, Tang B, Qin Y, Zhang JW, Zhang D, et al. Notch and Wnt signaling pathway in cancer: crucial role and potential therapeutic targets (review). Int J Oncol (2016) 48(2):437-49. doi:10.3892/ijo.2015.3280
166. Kulak O, Chen H, Holohan B, Wu X, He H, Borek D, et al. Disruption of Wnt/beta-catenin signaling and telomeric shortening are inextricable consequences of tankyrase inhibition in human cells. Mol Cell Biol (2015) 35(14):2425-35. doi:10.1128/MCB.00392-15
167. Kapoor N, Narayana Y, Patil SA, Balaji KN. Nitric oxide is involved in Mycobacterium bovis Bacillus Calmette-Guerin-activated Jagged1 and Notch1 signaling. J Immunol (2010) 184(6):3117-26. doi:10.4049/jimmunol.0903174
168. Manoranjan B, Venugopal C, McFarlane N, Doble BW, Dunn SE, Scheinemann K, et al. Medulloblastoma stem cells: where development and cancer cross pathways. Pediatr Res (2012) 71(4 Pt 2):516-22. doi:10.1038/pr.2011.62
169. Borggrefe T, Lauth M, Zwijsen A, Huylebroeck D, Oswald F, Giaimo BD. The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFbeta/BMP and hypoxia pathways. Biochim Biophys Acta (2016) 1863(2):303-13. doi:10.1016/j.bbamcr.2015.11.020
170. Mathieu M, Cotta-Grand N, Daudelin JF, Thebault P, Labrecque N. Notch signaling regulates PD-1 expression during CD8(+) T-cell activation. Immunol Cell Biol (2013) 91(1):82-8. doi:10.1038/icb.2012.53
171. Palaga T, Ratanabunyong S, Pattarakankul T, Sangphech N, Wongchana W, Hadae Y, et al. Notch signaling regulates expression of Mcl-1 and apoptosis in PPD-treated macrophages. Cell Mol Immunol (2013) 10(5):444-52. doi:10.1038/cmi.2013.22
172. Yuan X, Wu H, Xu H, Xiong H, Chu Q, Yu S, et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett (2015) 369(1):20-7. doi:10.1016/j.canlet.2015.07.048
173. Holla S, Ghorpade DS, Singh V, Bansal K, Balaji KN. Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-alpha-induced apoptosis. Mol Cancer (2014) 13:210. doi:10.1186/1476-4598-13-210
174. Burness CB. Sonidegib: first global approval. Drugs (2015) 75(13):1559-66. doi:10.1007/s40265-015-0458-y
175. Ghorpade DS, Holla S, Kaveri SV, Bayry J, Patil SA, Balaji KN. Sonic hedgehog-dependent induction of microRNA 31 and microRNA 150 regulates Mycobacterium bovis BCG-driven toll-like receptor 2 signaling. Mol Cell Biol (2013) 33(3):543-56. doi:10.1128/MCB.01108-12
176. Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel) (2016) 8(2):pii: E22. doi:10.3390/cancers8020022
177. Bansal K, Trinath J, Chakravortty D, Patil SA, Balaji KN. Pathogen-specific TLR2 protein activation programs macrophages to induce Wnt-beta-catenin signaling. J Biol Chem (2011) 286(42):37032-44. doi:10.1074/jbc.M111.260414
178. Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci (2004) 29(2):95-102. doi:10.1016/j.tibs.2003.12.004
179. Hu X, Paik PK, Chen J, Yarilina A, Kockeritz L, Lu TT, et al. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity (2006) 24(5):563-74. doi:10.1016/j.immuni.2006.02.014
180. Neumann J, Schaale K, Farhat K, Endermann T, Ulmer AJ, Ehlers S, et al. Frizzled1 is a marker of inflammatory macrophages, and its ligand Wnt3a is involved in reprogramming Mycobacterium tuberculosis-infected macrophages. FASEB J (2010) 24(11):4599-612. doi:10.1096/fj.10-160994
181. Martin M, Rehani K, Jope RS, Michalek SM. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol (2005) 6(8):777-84. doi:10.1038/ni1221
182. Lutay N, Hakansson G, Alaridah N, Hallgren O, Westergren-Thorsson G, Godaly G. Mycobacteria bypass mucosal NF-kB signalling to induce an epithelial anti-inflammatory IL-22 and IL-10 response. PLoS One (2014) 9(1):e86466. doi:10.1371/journal.pone.0086466
183. Taylor A, Harker JA, Chanthong K, Stevenson PG, Zuniga EI, Rudd CE. Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8(+) cytolytic T cell responses. Immunity (2016) 44(2):274-86. doi:10.1016/j.immuni.2016.01.018
184. Wang H, Huang S, Yan K, Fang X, Abussaud A, Martinez A, et al. Tideglusib, a chemical inhibitor of GSK3beta, attenuates hypoxic-ischemic brain injury in neonatal mice. Biochim Biophys Acta (2016) 1860(10):2076-85. doi:10.1016/j.bbagen.2016.06.027
185. Noh KT, Son KH, Jung ID, Kang TH, Choi CH, Park YM. Glycogen synthase kinase-3beta (GSK-3beta) inhibition enhances dendritic cell-based cancer vaccine potency via suppression of interferon-gamma-induced indoleamine 2, 3-dioxygenase expression. J Biol Chem (2015) 290(19):12394-402. doi:10.1074/jbc.M114.628578
186. Blok BA, Arts RJ, van Crevel R, Benn CS, Netea MG. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukoc Biol (2015) 98(3):347-56. doi:10.1189/jlb.5RI0315-096R
187. Lerm M, Netea MG. Trained immunity: a new avenue for tuberculosis vaccine development. J Intern Med (2015) 279(4):337-46. doi:10.1111/joim.12449
188. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Jacobs C, Xavier RJ, et al. BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin Immunol (2014) 155(2):213-9. doi:10.1016/j.clim.2014.10.005
189. van der Meer JW, Joosten LA, Riksen N, Netea MG. Trained immunity: a smart way to enhance innate immune defence. Mol Immunol (2015) 68(1):40-4. doi:10.1016/j.molimm.2015.06.019
190. Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. mTOR-and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science (2014) 345(6204):1250684. doi:10.1126/science.1250684
191. Gherardini L, Sharma A, Capobianco E, Cinti C. Targeting cancer with epi-drugs: a precision medicine perspective. Curr Pharm Biotechnol (2016) 17(10):856-65. doi:10.2174/1381612822666160527154757
192. Venza M, Visalli M, Catalano T, Beninati C, Teti D, Venza I. Epidrugs in the immunotherapy of cutaneous and uveal melanoma. Anticancer Agents Med Chem (2016) 16:1-16. doi:10.2174/1871520616666160425110401
193. Xiong F, Mou YZ, Xiang XY. Inhibition of mouse B16 melanoma by sodium butyrate correlated to tumor associated macrophages differentiation suppression. Int J Clin Exp Med (2015) 8(3):4170-4.
194. Vassilopoulos A, Fritz KS, Petersen DR, Gius D. The human sirtuin family: evolutionary divergences and functions. Hum Genomics (2011) 5(5):485-96. doi:10.1186/1479-7364-5-5-485
195. Wang J, Sinha T, Wynshaw-Boris A. Wnt signaling in mammalian development: lessons from mouse genetics. Cold Spring Harb Perspect Biol (2012) 4(5):pii: a007963. doi:10.1101/cshperspect.a007963
196. Mathern DR, Laitman LE, Hovhannisyan Z, Dunkin D, Farsio S, Malik TJ, et al. Mouse and human Notch-1 regulate mucosal immune responses. Mucosal Immunol (2014) 7(4):995-1005. doi:10.1038/mi.2013.118
197. Day CL, Tameris M, Mansoor N, van Rooyen M, de Kock M, Geldenhuys H, et al. Induction and regulation of T-cell immunity by the novel tuberculosis vaccine M72/AS01 in South African adults. Am J Respir Crit Care Med (2013) 188(4):492-502. doi:10.1164/rccm.201208-1385OC
198. Schaale K, Brandenburg J, Kispert A, Leitges M, Ehlers S, Reiling N. Wnt6 is expressed in granulomatous lesions of Mycobacterium tuberculosis-infected mice and is involved in macrophage differentiation and proliferation. J Immunol (2013) 191(10):5182-95. doi:10.4049/jimmunol.1201819
199. Poirier V, Bach H, v-Gay YA. Mycobacterium tuberculosis promotes anti-apoptotic activity of the macrophage by PtpA protein-dependent dephosphorylation of host GSK3alpha. J Biol Chem (2014) 289(42):29376-85. doi:10.1074/jbc.M114.582502
200. Richert-Spuhler LE, Lund JM. The immune fulcrum: regulatory T cells tip the balance between pro-and anti-inflammatory outcomes upon infection. Prog Mol Biol Transl Sci (2015) 136:217-43. doi:10.1016/bs.pmbts.2015.07.015