DISCOVERIES (ISSN 2359-7232), 2015, January-March issue

CITATION: 

Neagu M, Constantin C, Dumitrascu GR, Lupu AR, Caruntu C, Boda D, Zurac S. Inflammation markers in cutaneous melanoma - edgy biomarkers for prognosis. Discoveries 2015, Jan-Mar; 3(1): e38. DOI: 10.15190/d.2015.30

 Submitted: February 13, 2015; Revised: March 18, 2015; Accepted: March 19, 2015; Published: March 27, 2015;

 GO BACK to DISCOVERIES

Inflammation markers in cutaneous melanoma - edgy biomarkers for prognosis

Monica Neagu (1,2,*), Carolina Constantin (1), Georgiana Roxana Dumitrascu (1), Andreea Roxana Lupu (1), Constantin Caruntu (1,3), Daniel Boda (3), Sabina Zurac (4,5)

(1) Immunobiology Laboratory, “Victor Babes” National Institute of Pathology and Biomedical Sciences, Bucharest, Romania; (2) Faculty of Biochemistry, University of Bucharest; (3) Dermatology Research Laboratory, “Carol Davila” University of Medicine & Pharmacy, Bucharest, Romania; (4) Department of Pathology, "Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; (5) Colentina University Hospital, Bucharest, Romania

*Correspondence to: Dr. Habil. Monica Neagu, Immunobiology Laboratory, “Victor Babes” National Institute of Pathology, 99–101 Splaiul Independentei, 050096, Bucharest, Romania; Phone: +40213194528; 

Abstract

There is a fine balance between inflammation and tumorigenesis. While environmentally induced inflammatory condition can precede a malignant transformation, in other cases an oncogenic change of unknown origin can induce an inflammatory microenvironment that promotes the development of tumors. Regardless of its origin, maintaining the inflammation milieu has many tumor-promoting effects. As a result, inflammation can aid the proliferation and survival of malignant cells, can promote angiogenesis and metastasis, can down-regulate innate/adaptive immune responses, and can alter responses to hormones and chemotherapeutic agents. There is an abundance of studies unveiling molecular pathways of cancer-related inflammation; this wealth of information brings new insights into biomarkers domain in the diagnosis and treatment improvement pursue.

In cutaneous tissue there is an established link between tissue damage, inflammation, and cancer development. Inflammation is a self-limiting process in normal healthy physiological conditions, while tumorigenesis is a complex mechanism of constitutive pathway activation. Once more, in cutaneous melanoma, there is an unmet need for inflammatory biomarkers that could improve prognostication. Targeting inflammation and coping with the phenotypic plasticity of melanoma cells represent rational strategies to specifically interfere with metastatic progression. We have shown that there is a prototype of intratumor inflammatory infiltrate depicting a good prognosis, infiltrate that is composed of numerous T cells CD3+, Langerhans cells, few/absent B cells CD20+ and few/absent plasma cells. Circulating immune cells characterized by phenotype particularities are delicately linked to the stage melanoma is diagnosed in. Hence circulatory immune sub-populations, with activated or suppressor phenotype would give the physician a more detailed immune status of the patient. A panel of tissue/circulatory immune markers can complete the immune status, can add value to the overall prognostic of the patient and, as a result direct/redirect the therapy choice. The future lies within establishing low-cost, affordable/available, easily reproducible assays that will complete the pre-clinical parameters of the patient.

Access full text of the manuscript here: Full text (pdf)

References

1. Lindlahr H. Nature Cure Philosophy & Practice Based on the Unity of Disease & Cure, TWENTIETH EDITION, Published by The Nature Cure Publishing Company 525 South Ashland Boulevard, Chicago,1922.

2. Ward PA. Acute and Chronic Inflammation, in Charles N. Serhan, Peter A. Ward, Derek W. Gilroy Editors, Fundamentals of Inflammation, Cambridge University Press; 2010; 1-16.

3. 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 

4. Mantovani A, Allavena P, Sica A, Balkwill F.  Cancer-related inflammation, Nature 2008; 454: 436-444

5. Gonda TA, Tu S, Wang TC. Chronic inflammation, the tumor microenvironment and carcinogenesis. Cell Cycle 2009; 8:2005–2013.

6. Jiang H, Gebhardt C, Umansky L, Beckhove P, Schulze TJ, Utikal J, Umansky V. Elevated chronic inflammatory factors and myeloid-derived suppressor cells indicate poor prognosis in advanced melanoma patients. Int J Cancer. 2014. 

7. Neagu M. The immune system - a hidden treasure for biomarker discovery in cutaneous melanoma. In Gregory S. Makowski, editor: Advances in Clinical Chemistry, Burlington: Academic Press 2012; 58:89-140. 

8. Nedoszytko B, Sokolowska-Wojdylo M, Ruckemann-Dziurdzinska K, Roszkiewicz J, Nowicki RJ. Chemokines and cytokines network in the pathogenesis of the inflammatory skin diseases: atopic dermatitis, psoriasis and skin mastocytosis. Postep Derm Alergol 2014; XXXI, 2: 84–91.

9. Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV. In vitro cell migration and invasion assays. J Vis Exp. 2014; 88.

10. Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Lopez-Ramos D et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 2014; 507(7490):109-13. 

11. Bosanquet DC, Ye L, Harding KG, Jiang WG. Expressed in high metastatic cells (Ehm2) is a positive regulator of keratinocyte adhesion and motility: The implication for wound healing. J Dermatol Sci. 2013; 71(2):115-21.

12. Oser M, Yamaguchi H, Mader CC, Bravo-Cordero JJ, Arias M,  Chen X et al.  Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. JCB 2009; 186(4):4 571-587. 

13. Schafer M, Werner S. Cancer as an overhealing wound: An old hypothesis revisited. Nat. Rev. Mol. Cell. Biol. 2008; 9:628–638.

14. Turk BG, Bozkurt A, Yaman B, Ozdemir F, Unal I. Melanoma arising in chronic ulceration associated with lymphoedema. J Wound Care. 2013; 22(2):74-5.

15. Kong D, Li Y, Wang Z, Sarkar FH. Cancer Stem Cells and Epithelial-to-Mesenchymal Transition (EMT)-Phenotypic Cells: Are They Cousins or Twins?. Cancers (Basel) 2011;3 (1): 716–29.

16. Plikus MV, Guerrero-Juarez CF, Treffeisen E, Gay DL. Epigenetic control of skin and hair regeneration after wounding. Exp Dermatol. 2014.

17. Yan C, Grimm WA, Garner WL, Qin L, Travis T, Tan N, Han YP. Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol. 2010; 176(5): 2247-58.

18. Leopold PL, Vincent J, Wang H. A comparison of epithelial-to-mesenchymal transition and re-epithelialization. Semin Cancer Biol. 2012; 22(5-6):471-83.

19. Graf T, Enver T. Forcing cells to change lineages. Nature 2009; 462 (7273): 587–594.

20. Brittan M, Braun KM, Reynolds LE, Conti FJ, Reynolds AR, Poulsom R et al. Bone marrow cells engraft within the epidermis and proliferate in vivo with no evidence of cell fusion. J Pathol. 2005; 205:1–13.

21. Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol. 2008; 180:2581–7.

22. Uchiyama A, Yamada K, Ogino S, Yokoyama Y, Takeuchi Y, Udey MC et al. MFG-E8 regulates angiogenesis in cutaneous wound healing. Am J Pathol. 2014;184(7):1981-90.

23. Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 2010; 18:884–901.

24. Dunham LJ. Cancer in man at site of prior benign lesion of skin or mucous membrane: a review. Cancer Res. 1972; 32:1359–1374.

25. Zurac S, Negroiu G, Andrei R, Petrescu S, Tebeica T, Petre M et al. Inflammatory infiltrate in melanoma with regression as prognostic parameter, Virchows Archiv. 2013; 463(2):127-127.

26. Lopes RL, Borges TJ, Araújo JF, Pinho NG, Bergamin LS, Battastini AM et al. Extracellular mycobacterial DnaK polarizes macrophages to the M2-like phenotype. PLoS One 2014; 24;9(11):e113441.

27. Bønnelykke-Behrndtz ML, Steiniche T, Damsgaard TE, Georgsen JB, Danielsen A, Bastholt L et al. MelanA-negative spindle-cell associated melanoma, a distinct inflammatory phenotype correlated with dense infiltration of CD163 macrophages and loss of E-cadherin. Melanoma Res. 2015 Jan 19. 

28. Darling VR, Hauke RJ, Tarantolo S, Agrawal DK. Immunological effects and therapeutic role of C5a in cancer. Expert Rev Clin Immunol. 2015; 11(2):255-63. 

29. Qing X, Koo1 GC, Salmon JE. Complement regulates conventional DC-mediated NK-cell activation by inducing TGF-ß1 in Gr-1+ myeloid cells. Eur J Immunol. 2012; 42(7): 1723–1734.

30. Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, Gerard C, et al. Modulation of the antitumor immune response by complement. Nat. Immunol. 2008; 9:1225–1235. 

31. Neagu M, Constantin C, Zurac S. Immune parameters in prognosis and therapy monitoring of cutaneous melanoma patients - experience, role and limitations, BioMed Research International, special issue Molecular Biomarkers: Tools of Medicine (MBTM) Volume 2013, Article ID 107940.

32. Nguyen LT, Yen PH, Nie J et al. Expansion and characterization of human melanoma tumor-infiltrating lymphocytes (TILs). PLoS One 2010; 5(11): e13940.

33. Hussein MR, Elsers DA, Fadel SA, Omar AE. Immunohistological characterisation of tumour infiltrating lymphocytes in melanocytic skin lesions. Journal of Clinical Pathology, 2006; 59(3):316-324.

34. Azimi F, Scolyer RA, Rumcheva P et al., Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. Journal of Clinical Oncology 2012; 30(21):2678-2683.

35. Mihm Jr MC, Clemente CG, Cascinelli N, Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Laboratory Investigation 1996; 74:43-47.

36. Clemente CG, Mihm Jr MC, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 1996; 77:1303-1310.

37. Balch CM, Soong SJ, Gershenwald JE et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. Journal of Clinical Oncology 2001; 19: 3622-3634.

38. Taylor RC, Patel A, Panageas KS, Busam KJ, Brady MS. Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. Journal of Clinical Oncology 2007; 25:869-875.

39. Burton AL, Roach BA, Mays MP et al. Prognostic significance of tumor infiltrating lymphocytes in melanoma. The American Surgeon 2011; 77(2):188-192.

40. Oble DA, Loewe R, Yu P, Mihm Jr MC. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immunity 2009; 9:3.

41. Sarff M, Edwards D, Dhungel B, Wegmann KW, Corless C, Weinberg AD, Vetto JT. OX40 (CD134) expression in sentinel lymph nodes correlates with prognostic features of primary melanomas. Am J Surg. 2008; 195(5):621-5; discussion 625.

42. Chiou SH, Sheu BC, Chang WC, Huang SC, Hong-Nerng H. Current concepts of tumor-infiltrating lymphocytes in human malignancies. Journal of Reproductive Immunology 2005; 67:35-50.

43. Jørkov AS, Donskov F, Steiniche T et al., Immune response in blood and tumour tissue in patients with metastatic malignant melanoma treated with IL-2, IFN alpha and histamine dihydrochloride. Anticancer Research 2003; 23: 537-542.

44. Staquicini FI, Tandle A, Libutti SK, Sun J, Zigler M, Bar-Eli M et al. A Subset of Host B-Lymphocytes Control Melanoma Metastasis Through a MCAM/MUC18-dependent Interaction: Evidence from Mice and Humans. Cancer Res. 2008; 68(20):8419–8428.

45. van de Ven R, van den Hout MF, Lindenberg JJ et al. Characterization of four conventional dendritic cell subsets in human skin-draining lymph nodes in relation to T-cell activation. Blood. 2011;118(9):2502-2510.

46. Cochran AJ, Huang RR, Lee J, et al. Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol. 2006; 6(9):659-670.

47. Essner R, Kojima M. Dendritic cell function in sentinel nodes. Oncology (Williston Park). 2002; 16(1):27-31.

48. Gerlini G, Di Gennaro P, Mariotti G, Urso C, Chiarugi A, Caporale R et al. Human Langerhans cells are immature in melanoma sentinel lymph nodes. Blood 2012; 119 (20).

49. Haanen JB, Baars A, Gomez R et al. Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol Immunother 2006; 55(4): 451-458.

50. Ladányi A, Kiss J, Somlai B, Gilde K, Fejos Z, Mohos A et al. Density of DC-LAMP(+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother. 2007; 56(9):1459-69.

51. Newton-Bishop JA, Davies JR, Latheef F, Randerson-Moor J, Chan M, Gascoyne J et al.  25-Hydroxyvitamin D2 /D3 levels and factors associated with systemic inflammation and melanoma survival in the Leeds Melanoma Cohort. Int J Cancer. 2014; doi: 10.1002/ijc.29334. 

52. Bønnelykke-Behrndtz ML, Schmidt H, Christensen IJ, Damsgaard TE, Møller HJ, Bastholt L et al. Prognostic stratification of ulcerated melanoma: not only the extent matters. Am J Clin Pathol. 2014;142(6):845-56. 

53. Quereux G, Pandolfino MC, Knol AC, Khammari A, Volteau C, Nguyen JM, Dreno B. Tissue prognostic markers for adoptive immunotherapy in melanoma. Eur J Dermatol. 2007; 17(4):295-301. 

54. Neagu M, Constantin C, Tanase C. Immune-related biomarkers for diagnosis/prognosis and therapy monitoring of cutaneous melanoma. Expert Rev. Mol. Diagn. 2010; 10(7): 897–919.

55. Jennings L, Murphy GM, Predicting outcome in melanoma: where are we know?. British Journal of Dermatology 2009; 161: 496-503.

56. Ladányi A. Function and prognostic significance of immune cells infiltrating human tumors. Magy Onkol. 2004; 48(1):49-56.

57. Martins I, Sylla K, Deshayes F, Lauriol J, Ghislin S, Dieu-Nosjean MC et al. Coexpression of major histocompatibility complex class II with chemokines and nuclear NFkappaB p50 in melanoma: a rational for their association with poor prognosis. Melanoma Res. 2009; 19(4):226-37.

58. Bron LP, Scolyer RA, Thompson JF, Hersey P. Histological expression of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in human primary melanoma. Pathology 2004; 36(6):561-565.

59. Hernberg M, Mattila PS, Rissanen M, et al. The prognostic role of blood lymphocyte subset distribution in patients with resected high-risk primary or regionally metastatic melanoma. Journal of Immunotherapy 2007;  30(7):773-779.

60. Wang W, Edington HD, Rao UNM et al. Effects of High-Dose IFNa2b on Regional Lymph Node Metastases of Human Melanoma: Modulation of STAT5, FOXP3, and IL-17. Clinical Cancer Research 2008; 14(24): 8314-8320.

61. Nevala WK, Vachon CM, Leontovich AA, Scott CG, Thompson MA, Markovic SN, Evidence of systemic Th2 driven chronic inflammation in patients with metastatic melanoma. Clin Cancer Res.  2009; 15(6): 1931–1939.

62. Umanski V, Sevko A, Melanoma-induced immunosuppression and its meutralization, Seminars in Cancer Biology 2012; 22: 319-326.

63. Burkholder B, Huang RY, Burgess R, Luo S, Jones VS, Zhang W et al. Tumor-induced perturbation of cytokines and immune cells networks. Biochimica and Biophysica Acta 2014; 1845:182-201.

64. Menard C, Ghiringhelli F, Roux S, Chaput N, Mateus C, Grohmann U et al. CTLA-4 blockade confers lymphocyte resistance to regulatory T-cells in advanced melanoma: surrogate marker of efficacy of tremelimumab? Clin Cancer Res 2008; 14: 5242–5249.

65. Tarhini  AA, Edington H, Butterfield LH, Lin Y, Shuai Y, Tawbi H et al. Immune Monitoring of the Circulation and the Tumor Microenvironment in Patients with Regionally Advanced Melanoma Receiving Neoadjuvant Ipilimumab. PLOS One  2014 3;9(2):e87705. 

66. O’Connor GM, Hart OM, Gardiner CM. Putting the natural killer cells in its place. Immunology 2006; 117:1-10.

67. Nielsen N, Ødum N, Ursø B, Lanier LL, Spee P. Cytotoxicity of CD56bright NK Cells towards Autologous Activated CD4+ T Cells Is Mediated through NKG2D, LFA-1 and TRAIL and Dampened via CD94/NKG2A. PLoS One 2012; 7(2):e31959.

68. Kaur G, Trowsdale J, Fugger L. Natural killer cells and their receptor in multiple sclerosis. Brain 2013; 136:2657-2676

69. Singh S, Singh AP, Sharma B, Owen LB, Singh RK. CXCL8 and its cognate receptors in melanoma progression and metastasis. Future Oncol 2010; 6(1):111.

70. Ali TH, Pisanti S, Ciaglia E, Mortarini R, Anichini A, Garofalo C et al. Enrichment of CD56dimKIR+CD57+ highly cytotoxic NK cells in tumour-infiltrated lymph nodes of melanoma patients. Nature Communications  2014; 5:5639.

71. Messaoudene M, Fregni G, Fourmentraux-Neves E, Chanal J, Maubec E, Mazouz-Dorval S et al. Mature Cytotoxic CD56bright/CD16+ Natural Killer Cells Can Infiltrate Lymph Nodes Adjacent to Metastatic Melanoma. Cancer Res 2014; 74(1): 81-92.

72. Ballas ZK, Buchta CM, Rosean TR, Heusel JW, Shey MR. Role of NK Cell Subsets in Organ-Specific Murine Melanoma Metastasis. PLoS One 2013; 8(6): e65599.

73. Martens A, Zelba H, Garbe C, Pawelec G, Weide B. Monocytic myeloid-derived suppressor cells in advanced melanoma patients: Indirect impact on prognosis through inhibition of tumor-specific T-cell responses? OncoImmunology 2014; 3:e27845.

74. Haanen JB, Baars A, Gomez R et al. Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol Immunother 2006;  55(4):451-458.

75. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001; 19(16):3635-48.

76. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009; 27(36):6199-206. 

77. Weide B, Richter S, Büttner P, Leiter U, Forschner A, Bauer J et al. Serum S100B, lactate dehydrogenase and brain metastasis are prognostic factors in patients with distant melanoma metastasis and systemic therapy. PLoS One. 2013; 8(11):e81624. 

78. von Bauer R, Oikonomou D, Sulaj A, Mohammed S, Hotz-Wagenblatt A, Gröne HJ et al. CD166/ALCAM mediates proinflammatory effects of S100B in delayed type hypersensitivity. J Immunol. 2013; 191(1):369-77. 

79. Wevers KP, Kruijff S, Speijers MJ, Bastiaannet E, Muller Kobold AC, Hoekstra HJ. S-100B: a stronger prognostic biomarker than LDH in stage IIIB-C melanoma. Ann Surg Oncol. 2013; 20(8):2772-9. 

80. Dumitrascu G, Constantin C, Manda G, Hristescu S, Margaritescu I, Chirita D, Neagu M. Serum Markers in Skin Melanoma – Preliminary Study. Roum Arch Microbiol Immunol. 2009; 68(3):125-35

81. Vandooren B, Cantaert T, van Lierop MJ, Bos E, De Rycke L, Veys EM et al. Melanoma inhibitory activity, a biomarker related to chondrocyte anabolism, is reversibly suppressed by proinflammatory cytokines in rheumatoid arthritis. Ann Rheum Dis. 2009; 68(6):1044-50. 

82. Schmidt J, Riechers A, Stoll R, Amann T, Fink F, Spruss T, Gronwald W, König B, Hellerbrand C, Bosserhoff AK. Targeting melanoma metastasis and immunosuppression with a new mode of melanoma inhibitory activity (MIA) protein inhibition. PLoS One. 2012; 7(5):e37941.

83. Pang WW, Abdul-Rahman PS, Wan-Ibrahim WI, Hashim OH. Can the acute-phase reactant proteins be used as cancer biomarkers? Int J Biol Markers. 2010; 25(1):1-11.

84. Findeisen P, Zapatka M, Peccerella T, Matzk H, Neumaier M, Schadendorf D, Ugurel S. Serum amyloid A as a prognostic marker in melanoma identified by proteomic profiling. J Clin Oncol. 2009; 27(13):2199-208. 

85. Ros-Bullon MR, Sanchez Pedreno P, Martinez Liarte JH: Serum ceruloplasmin in melanoma patients. Anticancer Res. 2001; 21: 629-632.

86. Tarhini AA, Lin Y, Yeku O, LaFramboise WA, Ashraf M, Sander C, Lee S, Kirkwood JM. A four-marker signature of TNF-RII, TGF-a, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma. J Transl Med. 2014; 12:19. 

87. Hofmann MA, Kiecker F, Küchler I, Kors C, Trefzer U. Serum TNF-a, B2M and sIL-2R levels are biological correlates of outcome in adjuvant IFN-a2b treatment of patients with melanoma.  J Cancer Res Clin Oncol. 2011; 137(3):455-62. 

88. Porter GA, Abdalla J, Lu M , Smith S, Montgomery D, Grimm E et al. Significance of Plasma Cytokine Levels in Melanoma Patients With Histologically Negative Sentinel Lymph Nodes. Annals of Surgical Oncology.  2001; 8(2):116-122.

89. MacEwan DJ. TNF ligands and receptors – a matter of life and death. Br J Pharmacol. 2002; 135(4): 855–875. 

90. Ardestani S, Li B, Deskins DL, Wu H, Massion PP, Young PP. Membrane versus soluble isoforms of TNF-a exert opposing effects on tumor growth and survival of tumor-associated myeloid cells. Cancer Res. 2013; 73(13):3938-50. 

91. Hu X, Li B, Li X, Zhao X, Wan L, Lin G et al. Transmembrane TNF-a promotes suppressive activities of myeloid-derived suppressor cells via TNFR2. J Immunol. 2014; 192(3):1320-31. 

92. Polz J, Remke A, Weber S, Schmidt D, Weber-Steffens D, Pietryga-Krieger A et al. Myeloid suppressor cells require membrane TNFR2 expression for suppressive activity. Immun Inflamm Dis. 2014; 2(2):121-30. 

93. Chen X, Oppenheim JJ. TNF-a: an activator of CD4+FoxP3+TNFR2+ regulatory T cells. Curr. Dir. Autoimmun. 2010; 11: 119–134.

94. Neagu M, Constantin C, Martin D, Albulescu L, Iacob N, Ighigeanu D. Whole body microwave irradiation for improved dacarbazine therapeutical action in cutaneous melanoma mouse model. Radiology Research and Practice 2013; Article ID 414816, 10 pages.

95. Sanmamed MF, Carranza-Rua O, Alfaro C, Oñate C, Martín-Algarra S, G et al. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin Cancer Res. 2014; 15;20(22):5697-707. 

96. Tas F, Karabulut S, Yasasever CT, Duranyildiz D. Serum transforming growth factor-beta 1 (TGF-ß1) levels have diagnostic, predictive, and possible prognostic roles in patients with melanoma. Tumour Biol. 2014; 35(7):7233-7. 

97. Han G, Li F, Singh TP, Wolf P, Wang XJ. The pro-inflammatory role of TGFß1: a paradox? Int J Biol Sci. 2012;8(2):228-35. 

98. Neagu M, Constantin C. Immune-therapy in cutaneous melanoma – efficacy immune markers. in "Advancements in Tumor Immunotherapy and Cancer Vaccine ", pages 83-106, InTech, February 2012, ISBN 978-953-307-998-1. 

GO BACK to DISCOVERIES 
MEET OUR EDITORIAL BOARD 
SUBMIT A MANUSCRIPT

 Email us at info@discoveriesjournals.org if you have any questions.