Tumor-related interleukins: Old validated targets for new anti-cancer drug development

Molecular Cancer

Volumn 16, Issue 1, 2017, Pages

  Setrerrahmane, Sarra ^a   Xu, Hanmei ^a  

^a CHINA PHARMACEUTICAL UNIVERSITY   (China)

Author keywords

Anti cancer; Cancer; Cytokines; Immune cells; Tumor microenvironment

Indexed keywords

ANTINEOPLASTIC AGENT; CYTOKINE; DARLEUKIN; INTERLEUKIN 1; INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; INTERLEUKIN 2; INTERLEUKIN 4; INTERLEUKIN 4 RECEPTOR; INTERLEUKIN 6; MONOCLONAL ANTIBODY; RECOMBINANT INTERLEUKIN 15; RECOMBINANT INTERLEUKIN 21; BIOLOGICAL MARKER; INTERLEUKIN DERIVATIVE;

CANCER GROWTH; CANCER IMMUNOTHERAPY; CARCINOGENESIS; DRUG DESIGN; DRUG MECHANISM; DRUG TARGETING; HUMAN; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; IMMUNOREGULATION; IMMUNOSTIMULATION; INFLAMMATION; INTRACELLULAR SIGNALING; MALIGNANT NEOPLASM; MELANOMA; MOLECULAR PATHOLOGY; NONHUMAN; REVIEW; TUMOR GROWTH; TUMOR INVASION; TUMOR MICROENVIRONMENT; ANIMAL; DRUG DEVELOPMENT; DRUG EFFECT; GENE EXPRESSION REGULATION; GENETICS; IMMUNOLOGY; IMMUNOMODULATION; METABOLISM; MOLECULARLY TARGETED THERAPY; NEOPLASM; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOMARKERS; DRUG DISCOVERY; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; IMMUNOMODULATION; INTERLEUKIN-2; INTERLEUKINS; MOLECULAR TARGETED THERAPY; NEOPLASMS; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 85029748286     PISSN: None     EISSN: 14764598     Source Type: Journal    
DOI: 10.1186/s12943-017-0721-9     Document Type: Review

References (202)

1. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539-45.
2. Levine AM. AIDS-related malignancies. Curr Opin Oncol. 1994;6:489-91.
3. Shacter E, Weitzman SA. Chronic inflammation and cancer. Oncology. 2002;16:217.
4. Visser KED, Coussens ELM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6:24.
5. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. J Clin Investig. 2007;117:60-9.
6. Denardo DG, Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Research. 2007;9:212.
7. Elomar EM, Rabkin CS, Gammon MD, et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 2003;124:1193.
8. Negus RP, Stamp GW, Hadley J, et al. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. Am J Pathol. 1997;150:1723-34.
9. Luster AD, Alon R, von Andrian UH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol. 2005;6:1182.
10. Mantovani A, Sozzani, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549-55.
11. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137-48.
12. Pyfferoen L, Brabants E, Everaert C, et al. The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome[J]. OncoImmunology. 2017;6(1):e1253655.
13. Westergaard MCW, Andersen R, Kjeldsen JW et al. 54PDPreclinical Development of tumor-infiltrating lymphocytes (TILs) based adoptive cell transfer immunotherapy (ACT) for patients with advanced ovarian cancer. 2016.
14. Denardo D, Coussens L. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. 2007.
15. Sektioglu IM, Carretero R, Bulbuc N et al. Basophils promote tumor rejection via chemotaxis and infiltration of CD8+ T cells. Cancer Research. 2016;77:291.
16. Schwartz C, O'Grady K, Lavelle EC et al. Interleukin 33: an innate alarm for adaptive responses beyond Th2 immunity - emerging roles in obesity, intestinal inflammation and cancer. European Journal of Immunology. 2016;46:1091-1100.
17. Benbaruch A. Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. Semin Cancer Biol. 2006;16:38-52.
18. Kim R, Emi M, Tanabe K, et al. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 2006;66:5527.
19. de Visser KE, Coussens LM. The inflammatory tumor microenvironment and its impact on cancer development. Contrib Microbiol. 2006;13:118-37.
20. Nguyen DP, Li J, Tewari AK. Inflammation and prostate cancer: the role of interleukin 6 (IL-6). BJU Int. 2014;113:986-92.
21. Kumar J, Ward AC. Role of the interleukin 6 receptor family in epithelial ovarian cancer and its clinical implications. Biochim Biophys Acta. 1845;2014:117-25.
22. Dang HT, Budhu A, Wang XW. The origin of cancer stem cells. J Hepatol. 2014;60:1304.
23. Ishiko T, Mita S, Hidaka H et al. Human carcinoma cells express IL-8 and IL-8 receptor: their role and regulation in cancer biology. International Congress. 2003;1255:327-32.
24. Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014;70:11-20.
25. Malek TR. The biology of interleukin-2. Annu Rev Immunol. 2008;26:453.
26. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313:1485.
27. Lotze MT, Chang AE, Seipp CA, et al. High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. Responses, treatment-related morbidity, and histologic findings. JAMA. 1986;256:3117-24.
28. Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989;210:474.
29. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose Interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003;21:3127-32.
30. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192:5451-8.
31. Sim GC, Radvanyi L. The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev. 2014;25:377.
32. Rudensky AY, Regulatory T. Cells and Foxp3. Immunol Rev. 2011;241:260-8.
33. Leonard WJ, Krönke M, Peffer NJ, et al. Interleukin 2 receptor gene expression in normal human T lymphocytes. Proc Natl Acad Sci U S A. 1985;82:6281.
34. Kronin V, Vremec D, Shortman K. Does the IL-2 receptor alpha chain induced on dendritic cells have a biological function? Int Immunol. 1998;10:237-40.
35. Krieg C, Létourneau S, Pantaleo G, et al. Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc Natl Acad Sci. 2010;107:11906-11.
36. Siegel JP, Sharon M, Smith PL, et al. The IL-2 receptor beta chain (p70): role in mediating signals for LAK, NK, and proliferative activities. Science. 1987;238:75-8.
37. Bosco MC, Espinoza-Delgado I, Schwabe M, et al. Regulation by interleukin-2 (IL-2) and interferon gamma of IL-2 receptor gamma chain gene expression in human monocytes. Blood. 1994;83:2995-3002.
38. Wang HM, Smith KA. The interleukin 2 receptor. Functional consequences of its bimolecular structure. J Ex Med. 1987;166:1055.
39. Rickert M, Wang X, Boulanger MJ, et al. The structure of interleukin-2 complexed with its alpha receptor. Science. 2005;308:1477-80.
40. Takeshita T, Asao H, Ohtani K, et al. Cloning of the gamma chain of the human IL-2 receptor. Science. 1992;257:379-82.
41. Pipkin ME, Sacks JA, Cruzguilloty F et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity. 2010;32:91-103.
42. Sim GC, Martinorozco N, Jin L, et al. IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Investig. 2014;124:99.
43. Banchereau J, Pascual V, O'Garra A. From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat Immunol. 2012;13:925.
44. Fettelschoss A, Kistowska M, Leibundgut-Landmann S, et al. Inflammasome activation and IL-1β target IL-1α for secretion as opposed to surface expression. Proc Natl Acad Sci U S A. 2011;108:18055-60.
45. Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood. 2006;107:2409.
46. Rosenberg SA, Yang JC, White DE, et al. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228:307.
47. Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with Cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12:1005-16.
48. Baek S, Kim YM, Kim SB, et al. Therapeutic DC vaccination with IL-2 as a consolidation therapy for ovarian cancer patients: a phase I/II trial. Cell Mol Immunol. 2015;12:87-95.
49. Dudley ME, Rosenberg SA. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298:850-4.
50. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-Myeloablative but Lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23:2346.
51. Cavalieri S, Cazzaniga S, Geuna M et al. Human T lymphocytes transduced by lentiviral vectors in the absence of TCR activation maintain an intact immune competence. Blood. 2003;102:497-505.
52. Langerman A, Callender GG, Nishimura MI. Retroviral transduction of peptide stimulated t cells can generate dual t cell receptor-expressing (bifunctional) t cells reactive with two defined antigens. J Transl Med. 2004;2:42.
53. Xu Y, Zhang M, Ramos CA, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood. 2014;123:3750.
54. Zhu EF, Gai SA, Opel CF, et al. Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2. Cancer Cell. 2015;27:489.
55. Chaurasiya S, Hew P, Crosley P, et al. Breast cancer gene therapy using an adenovirus encoding human IL-2 under control of mammaglobin promoter/enhancer sequences. Cancer Gene Ther. 2016;23:178.
56. Tähtinen S, Blattner C, Vähä-Koskela M et al. T-Cell Therapy Enabling Adenoviruses Coding for IL2 and TNFα Induce Systemic Immunomodulation in Mice With Spontaneous Melanoma. Journal of Immunotherapy. 2016;39:343.
57. Weide B, Neri D, Elia G. Intralesional treatment of metastatic melanoma: a review of therapeutic options. Cancer Immunol Immunother. 2017;66:647-56.
58. Heaton KM, Ju G, Grimm EA. Human interleukin 2 analogues that preferentially bind the intermediate-affinity interleukin 2 receptor lead to reduced secondary cytokine secretion: implications for the use of these interleukin 2 analogues in cancer immunotherapy. Cancer Res. 1993;53:2597-602.
59. Marzec M, Liu X, Kasprzycka M, et al. IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes. Blood. 2008;111:2181.
60. De TD, Meazza R, Capaia M, et al. The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways. Blood. 2008;111:517.
61. Ochoa MC, Mazzolini G, Hervas-Stubbs S, et al. Interleukin-15 in gene therapy of cancer. Current Gene Therapy. 2013;13:15.
62. Cornish GH, Sinclair LV, Cantrell DA. Differential regulation of T-cell growth by IL-2 and IL-15. Blood. 2006;108:600-8.
63. Evans R, Fuller JA, Christianson G, et al. IL-15 mediates anti-tumor effects after cyclophosphamide injection of tumor-bearing mice and enhances adoptive immunotherapy: the potential role of NK cell subpopulations. Cell Immunol. 1997;179:66-73.
64. Yu P, Steel JC, Zhang M et al. Simultaneous blockade of multiple immune system inhibitory checkpoints enhances anti-tumor activity mediated by interleukin-15 in a murine metastatic colon carcinoma model. Clinical Cancer Research An Official Journal of the American Association for Cancer Research. 2010;16:6019.
65. Pfeiffer MM, Schumm M, Müller I, et al. IL-15-stimulated CD3|[sol]|CD19-depleted stem-cell boosts in relapsed pediatric patients after haploidentical SCT. Leukemia. 2012;26:2435-9.
66. Rettinger E, Bonig H, Wehner S, et al. Feasibility of IL-15-activated cytokine-induced killer cell infusions after haploidentical stem cell transplantation. Bone Marrow Transplant. 2013;48:1141-3.
67. Zeng R, Spolski R, Finkelstein SE, et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med. 2005;201:139.
68. Wang G, Tschoi M, Spolski R, et al. In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res. 2003;63:9016-22.
69. Hinrichs CS, Spolski R, Paulos CM, et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood. 2008;111:5326.
70. Res C. Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage malignancies. Cancer Res. 2011;71:3516-27.
71. Davis ID, Brady B, Kefford RF, et al. Clinical and biological efficacy of recombinant human interleukin-21 in patients with stage IV malignant melanoma without prior treatment: a phase IIa trial. Clin Cancer Res. 2009;15:2123-9.
72. Rider P, Carmi Y, Guttman O, et al. IL-1α and IL-1β recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol. 2011;187:4835.
73. Nakae S, Saijo S, Horai R, et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci. 2003;100:5986.
74. Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-ΚB pathway in the treatment of inflammation and cancer. J of Clin invest. 2001;107:135-142.
75. Wu Y, Zhou BP. Inflammation: a driving force speeds cancer metastasis. Chin J Lung Cancer. 2009;8:3267-73.
76. Jin L, Yuan RQ, Fuchs A, et al. Expression of interleukin-1beta in human breast carcinoma. Cancer. 1997;80:421-34.
77. Miller LJ, Kurtzman SH, Anderson K, et al. Interleukin-1 family expression in human breast cancer: Interleukin-1 receptor antagonist. Cancer Investig. 2000;18:293-302.
78. Wetzler M, Kurzrock R, Estrov Z, et al. Altered levels of interleukin-1 beta and interleukin-1 receptor antagonist in chronic myelogenous leukemia: clinical and prognostic correlates. Blood. 1994;84:3142.
79. Mitsunaga S, Ikeda M, Shimizu S, et al. Serum levels of IL-6 and IL-1|[beta]| can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 2013;108:2063-9.
80. Elaraj DM, Weinreich DM, Varghese S, et al. The role of interleukin 1 in growth and metastasis of human cancer xenografts. Clin Cancer Res. 2006;12:1088-96.
81. Apte RN, Voronov E. Is interleukin-1 a good or bad 'guy' in tumor immunobiology and immunotherapy? Immunol Rev. 2008;222:222-41.
82. Chen X, Lv Q, Hong Y, et al. IL-1β maintains the redox balance by regulating glutaredoxin 1 expression during oral carcinogenesis. J Oral Pathol Med. 2016;46:332-39.
83. Saijo Y, Tanaka M, Miki M, et al. Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction. J Immunol. 2002;169:469-75.
84. Jung YJ, Isaacs JS, Lee S, et al. IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. Faseb J. 2003;17:2115.
85. Saha B, Arase A, Imam SS, et al. Overexpression of E-cadherin and β-catenin proteins in metastatic prostate cancer cells in bone. Prostate. 2008;68:78-84.
86. Chung ST, Geerts D, Roseman K, et al. Osteoprotegerin mediates tumor-promoting effects of interleukin-1beta in breast cancer cells. Mol Cancer. 2017;16:27.
87. Baud'Huin M, Duplomb L, Teletchea S, et al. Osteoprotegerin: multiple partners for multiple functions. Cytokine Growth Factor Rev. 2013;24:401-9.
88. Holen I, Shipman CM. Role of osteoprotegerin (OPG) in cancer. Clin Sci. 2006;110:279-91.
89. Paquette B, Therriault H, Wagner JR. Role of interleukin-1β in radiation-enhancement of MDA-MB-231 breast cancer cell invasion. Radiat Res. 2013;180:292-8.
90. Han J, Bae SY, Oh SJ, et al. Zerumbone suppresses IL-1-induced cell migration and invasion by inhibiting IL-8 and MMP-3 expression in human triple-negative breast cancer cells. Chin J Rock Mech Eng. 2014;131:4862-3.
91. Holen I, Lefley DV, Francis SE, et al. IL-1 drives breast cancer growth and bone metastasis in vivo. Oncotarget. 2016;7:75571-5584.
92. Thomas S, Merchant S, Meade R et al. Abstract 2533: Interlukin-1 (IL-1) may induce prostate cancer (PCa) stem-like cells. 2016.
93. Elomar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398-402.
94. Karin M, Cao Y, Greten FR, et al. NF-ΚB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2:301-10.
95. Huang F, Chan AO, Rashid A et al. Interleukin-1β increases the risk of gastric cancer through induction of aberrant DNA methylation in a mouse model. Oncology Letters. 2016;11(4):2919-2924.
96. Economides AN, Carpenter LR, Rudge JS, Wong V, et al. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med. 2003;9:47-52.
97. Ratner M. IL-1 trap go-ahead. Nat Biotechnol. 2008;26:485.
98. Kishimoto T. The biology of interleukin-6. Blood. 1989;74:1-10.
99. Nagasaki T, Hara M, Nakanishi H, et al. Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer. 2014;110:469.
100. Rosejohn S, Scheller J, Elson G, et al. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80:227-36.
101. Kastritis E, Charidimou A, Varkaris A, et al. Targeted therapies in multiple myeloma. Target Oncol. 2009;4:23.
102. Adachi Y, Yoshio-Hoshino N, Nishimoto N. The blockade of IL-6 signaling in rational drug design. Curr Pharm Des. 2008;14:1217-24.
103. Duan Z, Feller AJ, Penson RT, et al. Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype. Clin Cancer Res. 1999;5:3445-53.
104. Duan Z, Lamendola DE, Penson RT, et al. Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-2OS human osteosarcoma cells. Cytokine. 2002;17:234-42.
105. Pu YS, Hour TC, Chuang SE, et al. Interleukin-6 is responsible for drug resistance and anti-apoptotic effects in prostatic cancer cells. Prostate. 2004;60:120-9.
106. Wang Y, Niu XL, Qu Y, et al. Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells. Cancer Lett. 2010;295:110.
107. Zou M, Zhang X, Xu C. IL6-Induced metastasis modulators p-STAT3, MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane in ovarian cancer cells. Cell Oncol. 2016;39:47.
108. Peng D, Tanikawa T, Li W, et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res. 2016;76:3156.
109. Ohara J, Paul WE. Receptors for B-cell stimulatory factor-1 expressed on cells of haematopoietic lineage. Nature. 1987;325:537-40.
110. Shi Y, Frost PJ, Hoang BQ, et al. IL-6-induced stimulation of c-myc translation in multiple myeloma cells is mediated by myc internal ribosome entry site function and the RNA-binding protein, hnRNP A1. Cancer Res. 2008;68:10215-22.
111. Lauta VM. Interleukin-6 and the network of several cytokines in multiple myeloma: an overview of clinical and experimental data. Cytokine. 2001;16:79.
112. Songür N, Kuru B, Kalkan F, et al. Serum interleukin-6 levels correlate with malnutrition and survival in patients with advanced non-small cell lung cancer. Tumori. 2004;90:196-200.
113. Altundag O, Altundag K, Gunduz E. Interleukin-6 and C-reactive protein in metastatic renal cell carcinoma. J Clin Oncol. 2005;23:1044. author reply 1044-1045
114. Negrier S, Perol D, Menetriercaux C, et al. Interleukin-6, Interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of Interleukin-6-from the Groupe Français d'Immunothérapie. J Clin Oncol. 2004;22:2371-8.
115. Garcia-Tuñón I, Ricote M, Ruiz A, et al. IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma. Histopathology. 2005;47:82-9.
116. Salgado R, Junius S, Benoy I, et al. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer. 2003;103:642-6.
117. Belluco C, Nitti D, Frantz M, et al. Interleukin-6 blood level is associated with circulating Carcinoembryonic antigen and prognosis in patients with colorectal cancer. Ann Surg Oncol. 2000;7:133-8.
118. Bellone S, Watts K, Cane' S, et al. High serum levels of interleukin-6 in endometrial carcinoma are associated with uterine serous papillary histology, a highly aggressive and chemotherapy-resistant variant of endometrial cancer. Gynecol Oncol. 2005;98:92-8.
119. Wei LH, Kuo ML, Chen CA, et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 2003;22:1517.
120. Zakrzewska I, Poznański J. Changes of serum il-6 and CRP after chemotherapy in patients with ovarian carcinoma. Pol Merkur Lekarski. 2001;11:210-3.
121. Penson RT, Kronish K, Duan Z, et al. Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel. Int J Gynecol Cancer. 2000;10:33-41.
122. Matsuoka Y, Nakayama H, Yoshida R, et al. TAMS and IL-6 contribute to resistance to radiotherapy in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2015;44:e261.
123. Culig Z, Steiner H, Bartsch G, et al. Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem. 2005;95:497-505.
124. Hara M, Nagasaki T, Shiga K et al. High serum levels of interleukin-6 in patients with advanced or metastatic colorectal cancer: the effect on the outcome and the response to chemotherapy plus bevacizumab. Surgery Today. 2016;7:483-489.
125. Ando K, Takahashi F, Motojima S, et al. Possible role for tocilizumab, an anti-interleukin-6 receptor antibody, in treating cancer cachexia. J Clin Oncol. 2013;31:69-72.
126. Wan S, Zhao E, Kryczek I, et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human Hepatocellular carcinoma stem cells. Gastroenterology. 2014;147:1393-404.
127. George DJ, Halabi S, Shepard TF, et al. The prognostic significance of plasma Interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480. Clin Cancer Res. 2005;11:1815-20.
128. He G, Dhar D, Nakagawa H, et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell. 2013;155:384-96.
129. Wang H, Lathia JD, Wu Q, et al. Targeting interleukin 6 signaling suppresses Glioma stem cell survival and tumor growth. Stem Cells. 2009;27:2393.
130. Sansone P, Storci G, Tavolari S, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Investig. 2007;117:3988.
131. Jono H, Shinriki S, Nakamura H, et al. Antitumor effect of humanized anti-interleukin. J Neurosurg. 2009;111:219-25.
132. Yao X, Huang J, Zhong H, et al. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2013;141:125-39.
133. Shinriki S, Jono H, Ota K, et al. Humanized anti-Interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral Squamous cell carcinoma. Clin Cancer Res. 2009;15:5426-34.
134. Shinriki S, Jono H, Ueda M, et al. Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma. J Pathol. 2011;225:142-50.
135. Rossi JF, Négrier S, James ND, et al. A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. Br J Cancer. 2010;103:1154-62.
136. Karkera J, Steiner H, Li W, et al. The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study §. Prostate. 2011;71:1455-65.
137. Fulciniti M, Hideshima T, Vermot-Desroches C, et al. A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clin Cancer Res. 2009;15:7144-52.
138. Moreau P, Harousseau JL, Wijdenes J, et al. A combination of anti-interleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rates in advanced multiple myeloma. Br J Haematol. 2000;109:661-4.
139. Rossi JF, Fegueux N, Lu ZY, et al. Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects. Bone Marrow Transplant. 2005;36:771.
140. Bayliss TJ, Smith JT, Schuster M, et al. A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Expert Opin Biol Ther. 2011;11:1663-8.
141. Heo TH, Wahler J, Suh N. Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer. Oncotarget. 2016;7:15460-73.
142. Chari A, Pri-Chen H, Jagannath S. Complete remission achieved with single agent CNTO 328, an anti-IL-6 monoclonal antibody, in relapsed and refractory myeloma. Clin Lymphoma Myeloma Leuk. 2013;13:333-7.
143. Markham A. Siltuximab: first global approval. Drugs. 2014;74:1147-52.
144. Kassar RCJ, Chan AW, Lilly LB, Al Habeeb A, Rotstein C. Leflunomide for the treatment of trichodysplasia spinulosa in a liver transplant recipient. Transpl Infect Dis. 2017;19:e12702.
145. Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46:1223-31.
146. Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012;119:4614-8.
147. Joshi BH, Leland P, Lababidi S, et al. Interleukin-4 receptor alpha overexpression in human bladder cancer correlates with the pathological grade and stage of the disease. Cancer Med. 2014;3:1615-28.
148. Prokopchuk O, Liu Y, Henne-Bruns D et al. Interleukin-4 enhances proliferation of human pancreatic cancer cells: evidence for autocrine and paracrine actions. British Journal of Cancer. 2005;92:921-28.
149. Todaro M, Lombardo Y, Francipane MG, et al. Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ. 2008;15:762.
150. Laporte SL, Juo ZS, Vaclavikova J, et al. Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell. 2008;132:259-72.
151. Willskarp M, Finkelman FD. Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Sci Signal. 2008;1:pe55.
152. Obiri NI, Debinski W, Leonard WJ, et al. Receptor for interleukin 13. Interaction with interleukin 4 by a mechanism that does not involve the common gamma chain shared by receptors for interleukins 2, 4, 7, 9, and 15. J Biol Chem. 1995;270:8797-804.
153. Murata T, Puri RK. Comparison of IL-13- and IL-4-induced signaling in EBV-immortalized human B cells. Cell Immunol. 1997;175:33-40.
154. Murata T, Husain SR, Mohri H, et al. Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway. Int Immunol. 1998;10:1103-10.
155. Luzina IG, Keegan AD, Heller NM, et al. Regulation of inflammation by interleukin-4: a review of "alternatives". J Leukoc Biol. 2012;92:753-64.
156. Ostrand-Rosenberg S, Grusby MJ, Clements VK. Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J Immunol. 2000;165:6015.
157. Ostrandrosenberg S, Sinha P, Clements V, et al. Signal transducer and activator of transcription 6 (Stat6) and CD1: inhibitors of immunosurveillance against primary tumors and metastatic disease. Cancer Immunol Immunother. 2004;53:86.
158. Kacha AK, Fallarino F, Markiewicz MA, et al. Cutting edge: spontaneous rejection of poorly immunogenic P1.HTR tumors by Stat6-deficient mice. J Immunol. 2001;165:6024-8.
159. Zhang WJ, Li BH, Yang XZ, et al. IL-4-induced Stat6 activities affect apoptosis and gene expression in breast cancer cells. Cytokine. 2008;42:39-47.
160. Tepper RI, Levinson DA, Stanger BZ, et al. IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice. Cell. 1990;62:457-67.
161. Hock H, Dorsch M, Kunzendorf U, et al. Mechanisms of rejection induced by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon gamma. Proc Natl Acad Sci. 1993;90:2774-8.
162. Gocheva V, Wang HW, Gadea BB, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 2010;24:241.
163. Vasiljeva O, Papazoglou A, Krüger A, et al. Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Res. 2006;66:5242.
164. Yan X, Li W, Pan L, et al. Lewis lung cancer cells promote SIGNR1(CD209b)-mediated macrophages polarization induced by IL-4 to facilitate immune evasion. J Cell Biochem. 2015;117:1158.
165. König A, Vilsmaier T, Rack B, et al. Determination of Interleukin-4, -5, -6, -8 and -13 in serum of patients with breast cancer before treatment and its correlation to circulating tumor cells. Anticancer Res. 2016;36:3123-30.
166. Purohit A, Newman SP, Reed MJ. The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Res. 2002;4:65-9.
167. Ginestier C, Min HH, Charafe-Jauffret E, et al. ALDH1 Is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555-67.
168. Dontu G, Abdallah WM, Foley JM, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003;17:1253-70.
169. Charafejauffret E, Ginestier C, Iovino F, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 2009;69:1302-13.
170. Razmkhah M, Jaberipour M, Erfani N, et al. Adipose derived stem cells (ASCs) isolated from breast cancer tissue express IL-4, IL-10 and TGF-β1 and upregulate expression of regulatory molecules on T cells: do they protect breast cancer cells from the immune response? Cell Immunol. 2011;266:116.
171. Uygur B, Leikina E, Chernomordik L. Abstract 925: IL-4 / IL-13 mediated cell-to-cell fusion in prostate cancer progress. Cancer Research. 2016;76:925-925.
172. Maeurer MJ, Martin DM, Castelli C, et al. Host immune response in renal cell cancer: Interleukin-4 (IL-4) and IL-10 mRNA are frequently detected in freshly collected tumor-infiltrating lymphocytes. Cancer Immunol Immunother. 1995;41:111-21.
173. Venmar KT, Carter KJ, Hwang DG, et al. IL-4 receptor ILR4α regulates metastatic colonization by mammary tumors through multiple signaling pathways. Cancer Res. 2014;74:4329-40.
174. Denardo D, Baretto J, Coussens L. CD4+ T cells regulate macrophage phenotype and functionally contribute to mammary tumor progression. Cancer Res. 2008;68:4196.
175. Iwashita J, Sato Y, Sugaya H, et al. mRNA of MUC2 is stimulated by IL-4, IL-13 or TNF-alpha through a mitogen-activated protein kinase pathway in human colon cancer cells. Immunol Cell Biol. 2003;81:275-82.
176. Todaro M, Alea MP, Stefano ABD, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of Interleukin-4. Cell Stem Cell. 2007;1:389.
177. Miklossy G, Hilliard TS, Turkson J. Therapeutic modulators of STAT signalling for human diseases. Nat Rev Drug Discov. 2013;12:611-29.
178. Rudolph J, Heine A, Quast T, et al. The JAK inhibitor ruxolitinib impairs dendritic cell migration via off-target inhibition of ROCK. Leukemia. 2016;30:2119-123.
179. Siemasko KF, Chong AS, Williams JW, et al. Regulation of B cell function by the immunosuppressive agent leflunomide. Transplantation. 1996;61:635.
180. Friedman OR, Kirkland TA, Woodroofe CC, et al. Deciphering the cellular targets of bioactive compounds using a Chloroalkane capture tag. ACS Chem Biol. 2015;10:2316.
181. Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature reviews. Drug discovery. 2005;4:988-1004.
182. Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130-9.
183. Bhadresha R. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368:2455-66.
184. Gibeon D, Menzies-Gow AN. Targeting interleukins to treat severe asthma. Expert Rev Respir Med. 2012;6:423-39.
185. Maes T, Joos GF, Brusselle GG. Targeting interleukin-4 in asthma: lost in translation? Am J Respir Cell Mol Biol. 2012;47:261-70.
186. Bankaitis KV, Fingleton B. Targeting IL4/IL4R for the treatment of epithelial cancer metastasis. Clin Exp Metastasis. 2015;32:847-56.
187. Mcdermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133.
188. Atkins MB, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordina. J Clin Oncol. 2008;26:5748-54.
189. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 Peptide vaccine and Interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119-27.
190. Radvanyi LG, Chantale B, Minying Z, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer. 2012;18:6758-70.
191. Liu KJ, Chao TY, Chang JY, et al. A phase I clinical study of immunotherapy for advanced colorectal cancers using carcinoembryonic antigen-pulsed dendritic cells mixed with tetanus toxoid and subsequent IL-2 treatment. J Biomed Sci. 2016;23:64.
192. Neri D, Weide B, Eigentler TK, et al. Intralesional treatment of stage III metastatic melanoma patients with L19-IL2: clinical and systemic immunological responses. Cancer Immunol Res. 2014;2:668-78.
193. Danielli R, Patuzzo R, Giacomo AMD, et al. Intralesional administration of L19-IL2/L19-TNF in stage III or stage IVM1a melanoma patients: results of a phase II study. Cancer Immunol Immunother. 2015;64:999.
194. Hong J, Wang H, Shen G, et al. Recombinant soluble gp130 protein reduces DEN-induced primary hepatocellular carcinoma in mice. Sci Rep. 2016;6:24397.
195. Quintás-Cardama A, Manshouri T, Estrov Z, et al. Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor. Investig New Drugs. 2011;29:818.
196. Enomoto A, Rho MC, Fukami A, et al. Suppression of cancer cachexia by 20S,21-epoxy-resibufogenin-3-acetate-a novel nonpeptide IL-6 receptor antagonist. Biochem Biophys Res Commun. 2004;323:1096-102.
197. Ostojic A, Vrhovac R, Verstovsek S. Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol. 2011;7:1035-43.
198. Teschner S, Burst V. Leflunomide: a drug with a potential beyond rheumatology. Immunotherapy. 2017;2:637-50.
199. Blakely K, Gooderham M, Papp K. Dupilumab, A Monoclonal Antibody for Atopic Dermatitis: A Review of Current Literature. Skin Therapy Lett. 2016;21:1.
200. Oh CK, Geba GP, Molfino N. Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma. Eur Respir Rev. 2010;19:46-54.
201. Borish LC, Nelson HS, Lanz MJ, et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med. 1999;160:1816-23.
202. Hart TK, Brigham-Burke M, Dede K, Al-Mahdi N, Zia-Amirhosseini P, Cook RM. Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol. 2002;130:93-100.