Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
5-Year IF – 2.0, IF – 1.9, JCI (2024) – 0.43
Scopus CiteScore – 4.3
Q1 in SJR 2024, SJR score – 0.598, H-index: 49 (SJR)
ICV – 161.00; MNiSW – 70 pts
Initial editorial assessment and first decision within 24 h

ISSN 1899–5276 (print), ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2011, vol. 20, nr 2, March-April, p. 137–148

Publication type: original article

Language: English

Immuno- and Hybridocytochemical Analysis of the Expression of Interleukin 2 and Its Receptor in Lung Cancers

Immuno- i hybrydocytochemiczna analiza ekspresji interleukiny 2 i jej receptora w nowotworach płuc

Karolina Sterzyńska1,, Aldona Kasprzak1,, Piotr Dzięgiel1,2,, Maciej Zabel1,2,

1 Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, Poland

2 Department of Histology and Embryology, Wroclaw Medical University, Wrocław, Polan

Abstract

Background. Interleukin 2 (IL-2) plays a significant role in the activation, differentiation and proliferation of hemopoietic cells, acting through a specific receptor complex (IL-2R). It is mainly produced by activated T helper cells (CD4+), but also by T cytotoxic lymphocytes (CD8+). Studies on IL-2/IL-2R in lung tumors focus mainly on detecting markers on immunocompetent cells isolated from patients’ blood. Only a few studies describe tissue expression of IL-2 and its receptor in lung cancers.
Objectives. This study aimed at examining the expression of IL-2 and its receptor (IL-2Rα and IL-2Rβ) in lung tumor cells and in T lymphocytes that infiltrate the tumors (TILs).
Material and Methods. The material for studies included archival paraffin blocks with the following types of lung tumors: typical and atypical carcinoids (TC, AC), small-cell lung carcinoma (SCLC), non-small-cell lung carcinoma, squamous carcinoma (NSCLC-SQ) and adenocarcinoma (ADENO). Expression of the markers was demonstrated using immunocytochemical and in situ hybridization techniques, and the obtained data were subjected to statistical analysis.
Results. Expression of IL-2, IL-2Rα and IL-2Rβ was noted in all the studied types of pulmonary tumors. A positive immunocytochemical reaction was observed both in the tumor cells and in the tumor-infiltrating lymphocytes. The presence of IL-2 and IL-2Rα was confirmed by the detection of mRNA for both markers. IL-2Rβ expression was detected mainly in cell cytoplasm, and IL-2Rα on cell membranes of both neoplastic cells and TILs. The most pronounced total expression of IL-2 and IL-2Rβ was demonstrated in lung carcinoids, and the most pronounced expression of IL-2Rα was noted in squamous cell carcinomas. The most pronounced “neoplastic” expression of IL-2 was observed in TC, and of IL-2Rα in atypical carcinoids. The most pronounced “neoplastic” expression of the IL-2Rβ subunit was detected in atypical pulmonary carcinoids, while the least pronounced expression of this subunit was detected in small-cell lung cancer.
Conclusion. The prevalent expression of IL-2 and IL-2Rβ in tumor cells and of IL-2Rα in tumor-infiltrating lymphocytes, regardless of the lung tumor involved, may suggest their autoand/or paracrine activity in the microenvironment of lung tumors. A direct relationship between the expression of the β subunit of IL-2R in tumor cells and tumor-infiltrating lymphocytes is observed in tumors of high proliferative activity (atypical carcinoids, small-cell and squamous pulmonary carcinomas).

Streszczenie

Wprowadzenie. Interleukina 2 (IL-2) odgrywa istotną rolę w aktywacji, różnicowaniu i proliferacji komórek hematopoetycznych, działając za pośrednictwem specyficznego kompleksu receptorowego (IL-2R). Jest wydzielana głównie przez aktywowane limfocyty T pomocnicze (CD4+), ale również przez limfocyty T cytotoksyczne (CD8+). Badania dotyczące IL-2/IL-2R w nowotworach płuc są głównie skupione na wykrywaniu tych markerów w komórkach immunokompetentnych izolowanych z krwi pacjentów. Nieliczne prace opisują tkankową ekspresję IL-2 i jej receptora w nowotworach płuc.
Cel pracy. Zbadano ekspresję IL-2 i jej receptora (IL-2Rα i IL-2Rβ) w komórkach zmienionych neoplastycznie (komórki guza płuc) oraz w limfocytach T naciekających guzy płuca (TILs).
Materiał i metody. Materiał do badań stanowiły archiwalne bloczki parafinowe z następującymi typami guzów płuc: rakowiaki typowe i atypowe (TC, AC), rak drobnokomórkowy (SCLC), rak płaskonabłonkowy (NSCLC-SQ) i rak gruczołowy (ADENO). Ekspresję markerów wykrywano z wykorzystaniem technik immunocytochemicznych i hybrydyzacji in situ. Wszystkie uzyskane dane poddano analizie statystycznej.
Wyniki. Ekspresję IL-2, IL-2Rα oraz IL-2Rβ wykrywano we wszystkich typach badanych nowotworów płuc. Pozytywną reakcję immunocytochemiczną obserwowano zarówno w komórkach nowotworowych, jak również w limfocytach infiltrujących guzy. Obecność IL-2 i IL-2Rα potwierdzono wykrywaniem mRNA dla obu markerów. Ekspresję IL-2Rβ umiejscowiano głównie w cytoplazmie komórek, a IL-2Rα na błonach komórkowych i to zarówno komórek neoplastycznych, jak i TILs. Największą całkowitą ekspresję IL-2 i IL-2Rβ wykazywały rakowiaki płuc, a IL-2Rα raki płaskonabłonkowe. Największą „guzową” ekspresję IL-2 obserwowano w TC, a IL-2Rα w atypowym rakowiaku płuc. Ekspresja „guzowa“ podjednostki β IL-2R również była największa w atypowym rakowiaku płuc, a najmniejsza dotyczyła drobnokomórkowego raka płuc.
Wnioski. Przeważająca ekspresja IL-2 i IL-2Rβ w komórkach guzowych, a IL-2Rα w limfocytach naciekających guz niezależnie od typu nowotworu płuc, może sugerować ich autoi/lub parakrynowe działanie w mikrośrodowisku guza płuc. Wprost proporcjonalna zależność między ekspresją podjednostki β IL-2R w komórkach guza i w TILs dotyczy nowotworów płuc o dużej aktywności proliferacyjnej (atypowe rakowiaki, drobnokomórkowe i płaskonabłonkowe raki płuc).

Key words

interleukin 2, receptor of interleukin 2, lung cancers

Słowa kluczowe

interleukina 2, receptor interleukiny 2, raki płuc

References (30)

  1. Morgan DA, Ruscetti F, Gallo R: Selective in vitro growth of T lymphocytes from normal human bone marrow. Science 1976, 193, 1007–1008.
  2. Nelson BH: IL-2 regulatory T cells, and tolerance. J Immunol 2004, 172, 3983–3988.
  3. Kuhn DJ, Ping Dou Q: The role of interleukin-2 receptor alpha in cancer. Front Biosci 2005, 10, 1462–1474.
  4. Lin WC, Yasumura S, Suminami Y, Sung MW, Nagashima S, Stanson J, Whiteside TL: Constitutive production of IL-2 by human carcinoma cells, expression of IL-2 receptor, and tumor cell growth. J Immunol 1995, 155, 4805–4816.
  5. Minami Y, Oishi I, Liu Z, Nakagawa S, Miyazaki T, Taniguchi T: Signal transduction mediated by the reconstituted IL-2 receptor. J Immunol 1994, 152, 5680–5690.
  6. Taniguchi T, Minami Y: The IL-2/IL-2 receptor system: A current overview. Cell 1993, 73, 5–8.
  7. Baier PK, Wolff-Vobeck G, Eggstein S, Baumgartner U, Hopt UT: Cytokine expression in colon carcinoma. Anticancer Res 2005, 25, 2135–2139.
  8. Bien E, Balcerska A: Serum soluble interleukin 2 receptor alpha in human cancer of adults and children: a review. Biomarkers 2007, 28, 1–26.
  9. De Vita F, Turitto G, di Grazia M, Frattolillo A, Catalano G: Analysis of interleukin-2/interleukin-2 receptor system in advanced non-small cell lung cancer. Tumori 1998, 84, 33–38.
  10. Kuhn DJ, Smith DM, Pross S, Whiteside TL, Dou QP: Overexpression of interleukin-2 receptor in a human squamous cell carcinoma of the head and neck cell line is associated with increased proliferation, drug resistance, and transforming ability. J Cell Biochem 2003, 89, 824–836.
  11. Lissoni P, Barni S, Rovelli F, Rescaldani R, Rizzo V, Biondi A, Tancini G: Correlation of serum interleukin-2 levels, soluble interleukin-2 receptors and T lymphocyte subsets in cancer patients. Tumori 1990a, 76, 14–17.
  12. Tisi E, Lissoni P, Angeli M, Arrigoni C, Corno E, Cassina E, Ballabio D, Benenti C, Barni S, Tancini G: Postoperative increase in soluble interleukin-2 receptor serum levels as predictor for early recurrence in non-small lung carcinoma. Cancer 1992, 69, 2458–2462.
  13. Olejniczak K, Kasprzak A: Biological properties of interleukin 2 and its role in pathogenesis of selected diseases – a review. Med Sci Monit 2008, 14, 179–189.
  14. Reichert TE, Watkins S, Stanson J, Johnson JT, Whiteside TL: Endogenous IL-2 in cancer cells: a marker of cellular proliferation. J Histochem Cytochem 1998, 46, 603–611.
  15. Żeromski J: Significance of tumor-cell receptors in human cancer. Arch Immunol Therap Exp 2002, 50, 105–110.
  16. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer Statistics, 2009. Ca Cancer J Clin 2009, 59, 225–249.
  17. Fischer JR, Schindel M, Stein N, Lahm H, Gallati H, Krammer PH, Drings P: Selective suppression of cytokine secretion in patients with small-cell lung cancer. Ann Oncol 1995, 6, 921–926.
  18. Lissoni P, Barni S, Rovelli F, Viviani S, Maestroni GJ, Conti A, Tancini G: The biological significance of soluble interleukin-2 receptors in solid tumors. Eur J Cancer 1990b, 26, 33–36.
  19. Fischer JR, Schindel M, Bulzebruck H, Lahm H, Krammer PH, Drings P: Decrease of interleukin-2 secretion is a new independent prognostic factor associated with poor survival in patients with small-cell lung cancer. Ann Oncol 1997, 8, 457–461.
  20. Huang M, Wang J, Lee P, Sharma S, Mao JT, Meissner H, Uyemura K, Modlin R, Wollman J, Dubinett SM: Human non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Res 1995, 55, 3847–3853.
  21. Ortegel JW, Staren ED, Faber LP, Warren WH, Braun DP: Modulation of tumor-infiltrating lymphocyte cytolitic activity against human non-small cell lung cancer. Lung Cancer 2002, 36, 17–25.
  22. Li R, Rüttinger D, Li R, Si LS, Wang YL: Analysis of the immunological microenvironment at the tumor site in patients with non-small cell lung cancer. Langenbecks Arch Surg 2003, 388, 406–412.
  23. Yanelli JR, Tucker JA, Hidalgo G, Perkins S, Kryscio R, Hirschowitz EA: Characteristics of PBMC obtained from leukapheresis products and tumor biopsies of patients with non-small cell lung cancer. Oncol Rep 2009, 22, 1459–1471.
  24. Hsu S, Raine L, Fanger H: Use a avidin-biotin peroxidase complex (ABC) in immunoperoxidase techniques. J Histochem Cytochem 1981, 29, 577–580.
  25. Remmele W, Stegner HE: Vorschlag zur einheitlichen Definition eines immunreaktiven Score (IRS) fur den Immunohistochemichen Ostrogenrezeptor-Nachweis (ER-ICA) im Mammikarzinomgewebe. Patologie 1987, 8, 138–140.
  26. Yesner R: Heterogeneity of so-called neuroendocrine lung tumors. Exp Mol Pathol 2001, 70, 179–182.
  27. Gutgsell NS, Malek TR: Formation of high affinity IL-2 receptors is dependent on a nonligand binding region of the α subunit. J Immunol 1994, 153, 3899–3907.
  28. Garcia-Tunnon J, Ricote M, Ruiz A, Fraile B, Paniagua R, Royuela M: Interleukin-2 and its receptor complex in situ and infiltrative human breast cancer: an immunohistochemical comparative study. Breast Cancer Res 2004, 6, 1–7.
  29. Marc MM, Korosec P, Kern I, Sok M, Ihan A, Kosnik M: Lung tissue and tumor-infiltrating T lymphocytes in patients with non-small cell lung carcinoma and chronic obstructive pulmonary disease (COPD): moderate/severe versus mild stage of COPD. Scand I Immunol 2007, 66, 694–702.
  30. Trentin L, Zambello R, Bulian P, Cerutti A, Milani A, Pirone E, Nitti D, Agostini C, Semenzato G: Functional role of IL-2 receptors on tumor-infiltrating lymphocytes. Br J Cancer 1994, 69, 1046–1051.
© Wroclaw Medical University