The changes of angiogenesis and immune regulations in stromal microenvironment of cutaneous melanomas
Authors:
Vladimír Židlík 1,2,3; Magdalena Uvírová 1; Robert Ondruššek 1,2; Jana Dvořáčková 1,2; Svetlana Brychtová 3,4
Authors place of work:
CGB laboratoř, a. s., Ostrava
1; Ústav patologie FN Ostrava, Ostrava
2; Ústav klinické a molekulární patologie LF UP Olomouc
3; Ústav molekulární a translační medicíny LF UP Olomouc
4
Published in the journal:
Čes.-slov. Patol., 55, 2019, No. 3, p. 170-175
Category:
Original Articles
Summary
Tumour microenvironment contributes to growth and metastasis, where angiogenesis and immune alteration suppressing its effectory function belong to main factors. Our study is focused on an analysis of microvascular density (MVD), quantification of FOXP3+ T regulatory lymphocytes (Tregs) and PD-L1 lymphocytes, which are associated with a tumour-cells immune escape mechanism. We examined 95 cutaneous melanomas devided in four groups according to TNM classification - pT1 (35), pT2 (21), pT3 (21), pT4 (18) and 25 melanocytic nevi as a control group. Investigated parameters were detected on paraffin embedded tissues by indirect immunohistochemistry, and evaluated by light microscope in central (C) and at peripheral regions (P) on a 1mm2 „hot spot“ region (the area of the highest density). We found a significant MVD increase correlating with a stage of disease, mostly at the edge of tumours (p=0,0001). Lymphocytic PD-L1 expresion was increased in melanomas of pT3 and pT4 stages, also predominantly at the periphery of lesions (p=0,0001). Numbers of FOXP3 lymphocytes positively correlated with a melanoma stage, where higher values were observed in central areas (p=0,008). Our study documents that stimulation of angiogenesis and induction of an adaptive immune response correlate with a melanoma stage. The most prominent changes are at the tumour periphery confirming heterogeneity of a tumour stroma, which is more prominent in advanced tumours, and which may contribute to higher agresivity of these stages.
Keywords:
Nestin – Angiogenesis – CD90 – FOXP3 – Tregs – PD-L1 – TIL
Zdroje
1. Rejthar A, Vojtěšek B. Obecná patologie nádorového růstu. GRADA Publishing, spol. s r. o., 2002, 24-25.
2. Tarin D. Role of the host stroma in cancer an its therapeutic significance. Cancer Metastasis Rev 2013; 32(3-4): 553-566.
3. Brychtová S, Bezděková M, Hirňák J, Sedláková E, Tichý M, Brychta T. Stromal microenvironment alterations in malignant melanoma. IntechOpen, https://www.intechopen.com/books/research-on-melanoma-a-glimpse-into-current-directions-and-future-trends/stromal-microenvironment-alterations-in-malignant-melanoma.
4. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature 2004;18; 432(7015): 332–337.
5. Pastushenko I, Vermeulen PB, Carapeto FJ, et al. Blood microvessel density, lymphatic microvessel density and lymphatic invasion in predicting melanoma metastases: systematic review and meta-analysis. Br J Dermatol 2014; 170(1): 66-77.
6. Ria R, Reale A, Castrovilli A, et al. Angiogenesis and progression in human melanoma. Dermatol Res Pract 2010; 2010: 185687.
7. Matsuda Y, Hagio M, Ishiwata T. Nestin: A novel angiogenesis marker and possible target for tumor angiogenesis. World J Gastroenterol 2013; 19(1): 42–48.
8. Kerr EH, Wang D, Lewis JS Jr., Said-Al-Naief N, Hameed O. Lack of correlation between microvascular density and pathological features and outcomes in sinonasal and oral mucosal melanomas. Head and Neck Pathol 2011; 5: 199-204.
9. Ishiwata T, Matsuda Y, Naito Z. Nestin in gastrointestinal and other cancers: effects on cells and tumor angiogenesis. World J Gastroenterol 2011; 17(4): 409–418.
10. Kumar A, Bhanja A, Bhattacharyya J, Jaganathan BG. Multiple roles of CD90 in cancer. Tumour Biol 2016; 37(9): 11611-11622.
11. Schubert K, Gutknecht D, Köberle M, Anderegg U, Saalbach A. Melanoma cells use Thy-1 (CD90) on endothelial cells for metastasis formation. Am J Pathol 2013; 182(1): 266-276.
12. Nico B, Benaggiano V, Mangieri D, Maruotti N, Vacca A, Ribatti D. Evaluation of microvascular density in tumors: pro and contra. Histol Histopathol 2008; 23(5): 601-607.
13. Ohkura N, Sakaguchi S. Regulatory T cells: roles of T cell receptor for their development and function. Semin Immunopathol 2010; 32: 95-106.
14. Oble DA, Loewe R, Yu P, Minhm MC Jr. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun 2009; 9: 3.
15. Titu LV, Monson JRT, Greenman J. The role of CD8(+) T cells in immune responses to colorectal cancer. Cancer Immunol Immunother 2002; 51: 235-247.
16. DiPaolo RJ, Glass DD, Bijwaard KE, Shevach EM. CD4+CD25+ T cells prevent the development of organ-specific autoimmune disease by inhibiting the differentiation of autoreactive effector T cells. J Immunol 2005; 175: 7135-7142.
17. Tan B, Anaka M, Deb S, et al. FOXP3 over-expression inhibits melanoma tumorigenesis via effects on proliferation and apoptosis. Oncotarget 2014; 5(1):264-276.
18. Fu S, Zhang N, Yopp AC, et al. TGF-β induces FOXP3+ T-regulatory cells from CD4+CD25- precursors. Am J Transplant 2004; 4: 1614-1627.
19. Wang X, Cui Y, Luo G, et al. Activated mouse CD4+FOXP3- T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK-cell cytotoxicity. Cell Research 2012; 22: 1696-1706.
20. Floess S, Freyer J, Siewert C, et al. Epigenetic control of the FOXP3 locus in regulatory T cells. PLOS Biology, 2007; 5(2), e38.
21. Kim M, Grimmig T, Grimm M, et al. Expression of FOXP3 in colorectal cancer but not in Treg cells correlates with disease progression in patients with colorectal cancer. PLOS ONE, January 2013; 8(1), e53630.
22. Niu J, Jiang C, Li C, et al. FOXP3 expression in melanoma cells as a possible mechanism of resistance to immune destruction. Cancer Immunol Immunother 2011; 60: 1109-1118.
23. Apostolou I, Verginis P, Kretschmer K, Polansky J, Hühn J, von Boehmer H. Peripherally induced Treg: mode, stability, and role in specific tolerance. J Clin Immunol 2008; 28: 619-624.
24. Pacholczyk R, Kern J. The T-cell receptor repertoire of regulatory T cells. Immunology 2008; 125: 450-458.
25. Sakaguchi, S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T. Regulatory T cells: how do they suppress immune responses? Int Immunol 2009; 21(10): 1105-1111.
26. Zatloukalová P, Pjechová M, Babčanová S, Hupp TH, Vojtěšek B. Úloha PD-1/PD-L1 signalizace v protinádorové imunitní odpovědi. Klin Onkol 2016; 29(Suppl 4): 72-77.
27. Šťastný M, Říhová B. Únikové strategie nádorů pozornosti imunitního systému. Klin Onkol 2015; 28 (Suppl 4): 28–37.
28. Remon J, Chaput N, Planchard D. Predictive biomarkers for programmed death-1/programmed death ligand immune checkpoint inhibitors in nonsmall cell lung cancer. Curr Opin Oncol/CZ 2016; 28: 122-129.
29. Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol 2016; 47(1): 78-84.
30. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313(5795): 1960-1964.
31. Brychtová S, Fiurášková M, Hlobilková A, Brychta T, Hirňák J. Nestin expression in cutaneous melanomas and melanocytic nevi. J Cutan Pathol 2007; 34(5): 370-375.
32. Albini A, Bruno A, Gallo C, Pajardi G, Noonan DM, Dallaglio K. Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity. Connect Tissue Res 2015; 56(5): 414-42.
33. Ahmed F, Haass NK. Microenvironment-driven dynamic heterogeneity and phenotypic plasticity as a mechanism of melanoma therapy resistance. Front Oncol 2018; 8: 173.
34. Veselá P, Tonar Z, Boudová L. Mikrovaskulární denzita v lymfomech – hodnocení a klinický význam. Cesk Patol 2015; 51(2): 94-98.
35. Zhang S, Zhang D, Sun B. Vasculogenic mimicry: current status and future prospects. Cancer Lett 2007; 254(2): 157-164.
36. Baumgartner J, Wilson C, Palmer B, Richter D, Banerjee A, McCarter M. Melanoma induces immunosuppression by upregulating FOXP3+ regulatory T cells. J Surg Res 2007; 141(1): 72-77.
37. Wilke CM, Wu K, Zhao E, Wang G, Zou W. Prognostic significance of regulatoy T cells in tumor. Int Cancer 2010; 127(4): 748-758.
38. Li Z, Dong P, Ren M, et al. PD-L1 expression is associated with tumor FOXP3+ reglatory T-cell infiltration of breast cancer and poor prognosis of patient. J Cancer 2016; 7(7): 784–793.
39. Vassilakopoulou M, Avgeris M, Velcheti V, et al. Evaluation of PD-L1 expression and associated tumor-infiltrating lymphocytes in laryngeal squamous cell carcinoma. Clin Cancer Res 2016; 22(3): 704-713.
40. Kim HR, Ha SJ, Hong MH, et al. PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients. Scientific Reports 2016; 6: 36956.
41. Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer 2011; 117(10): 2192-2201.
42. Chlopik A, Selim MA, Peng Y, et al. Prognostic role of tumoral PDL-1 expression and peritumoral FOXP3+ lymphocytes in vulvar melanomas. Hum Pathol 2018; 73: 176-183.
43. Kraft S, Fernandez-Figueras MT, Richarz NA, Flaherty KT, Hoang MP. PD-L1 expression in desmoplastic melanoma is associated with tumor aggressiveness and progression. J Am Acad Dermatol 2017; 77(3): 534-542.
Štítky
Anatomical pathology Forensic medical examiner ToxicologyČlánok vyšiel v časopise
Czecho-Slovak Pathology
2019 Číslo 3
Najčítanejšie v tomto čísle
- Cytological examination of cerebrospinal fluid
- Neuronal ceroid lipofuscinosis with cardiac involvement
- Pituitary adenomas – practical approach to the diagnosis and the changes in the 2017 WHO classification
- Metanephric adenoma. A case report and literature review