The purpose of the study was to investigate the IL-2/IL-2 receptor system in patients with advanced non-small-cell lung cancer (NSCLC).
Patients and methods
Sera from 40 subjects and 80 patients with stage III and IV NSCLC were assayed for soluble interleukin-2 receptor (sIL-2R) and interleukin-2 (IL-2) by the enzyme-linked immunosorbent assay. Circulating CD25+ cells were analyzed by flow cytoflorimetry. The data were related to clinical status by comparing the levels of slL-2R and IL-2 at diagnosis and during the treatment.
Results
The mean slL-2R concentrations of the NSCLC patients were significantly higher than the control population (P=0.0001); the patients with metastatic disease had significantly higher levels than those with locally advanced disease (P=0.02). No correlation was seen between circulating CD25+ cells and slL-2R levels. Disease progression was associated with an increase in slL-2R levels and a decline in IL-2; the sIL-2R/IL-2 ratio showed a gradual increase with tumor progression.
Conclusions
Our study demonstrates in a large series of patients that in advanced NSCLC there is an imbalance of the IL-2/IL-2 receptor system. Furthermore, circulating slL-2R levels and the sIL-2R/IL-2 ratio may be useful as markers of disease activity and treatment response, suggesting a potential prognostic value.
AggarwalB.B., GuttermannJ.U.: Human Cytokine: Handbook for Basic and Clinical Research.Blackwell Scientific Publications, Cambridge, MA, 1992.
2.
ArmitageP., BerryG.: Statistical Methods in Medical Research, pp. 200–205, Oxford, Blackwell Scientific,1987.
3.
BennettM.A., StanfordJ.F., WhimsterW.F., WilliamsF.: Prostaglandins and human lung carcinoma.Br. J. Cancer,46: 888–893, 1982.
4.
BrayR.A., BrahmeZ.: Role of lipoxygenation in human natural killer cell activation.J. Immunonol.136: 1783–1790, 1986.
5.
CozzolinoF., TorciaM., AldimucciD., CarossinoA.M.: Mechanisms of suppression in lymph nodes from patients with solid tumors. In: Strategies in Cancer Medical Therapy: Biological Bases and Clinical Implications.AmadoriD., Ra-vaioliA., RidolfiR. (Eds.), pp. 233–242, Edimes, Pavia, 1989.
6.
DamleR.N., AdvaniS.M., GangalS.G.: Analysis of regulation of T cell responses by soluble inhibitory factors from the sera of patients with Hodgkin's disease.Int. J. Cancer,50: 192–196, 1992.
7.
DummerR., NestleF., SchaferE., WiedeJ., RogerJ., HartmannA.A., BurgG.: Influence of soluble interleukin-2 receptors and soluble CD8 proteins on natural killer cell activity and clinical course in cutaneous T-cell lymphoma patients.Arch. Dermatol. Res.,8: 557–562, 1990.
8.
DummerR., PosseckertG., NestleF., WitzgallR., BurgerM., BeckerJ.C.: Soluble interleukin-2 dependent proliferation and cytotoxicity: explanation for diminished natural killer cell activity in cutaneous T-cell lymphomas in vivo? J.Invest. Dermatol.,98: 50–54, 1992.
9.
DunlapN.E., LaneV.G., CloudG., TildenA.: In vitro NK and LAK activity in patients with bronchogenic carcinoma.Cancer,66: 1499–1504, 1990.
10.
HakimA.A.: Peripheral blood lymphocytes from patients with cancer lacking interleukin-2 (IL-2) receptor expression: isolation of mRNA enconding IL-2R.Cancer Detect. Prev.,12: 59–71, 1988.
11.
IngeT.H., HooverS.K., SusskindB.M., BanetS.K., BearH.D.: Inhibition of tumor-specific cytotoxic T lymphocyte responses by transforming growth factor β1.Cancer Res.,52: 1386–1392, 1992.
12.
JonesM., PhilipT., PalmerP., Von der MaaseH., VinkeJ., ElsonP., FranksC.R., SelbyP.: The impact of interleukin-2 on survival in renal cancer: a multivariate analysis.Cancer Biother.,8: 275–288, 1993.
13.
LauS.S., McMahonJ.B., McMenaminM.G., SchullerH.M., BoydM.R.: Metabolism of arachidonic acid in human lung cancer cell lines.Cancer Res.,47: 3757–3762, 1987.
14.
Le FeverA.V., FunahashiA.: Phenotype and function of natural killer cells in patients with bronchogenic carcinoma.Cancer Res.,51: 5596–5601, 1991.
15.
LissoniP., BarniS., RovelliF., TanciniG.: Lower survival in metastatic cancer patients with reduced interleukin-2 blood concentrations.Oncology,48: 125–127, 1991.
16.
LissoniP., BarniS., RovelliF., VivianiS., MaestroniG.M., ContiA., TanciniG.: The biological significance of soluble interleukin-2 receptors in solid tumors.Eur. J. Cancer,26: 33–36, 1990.
17.
LissoniP., TisiE., BrivioF., BarniS., RovelliF., PeregoM., TanciniG.: Increase in soluble interleukin-2 receptor and neopterin serum levels during immunotherapy of cancer with interleukin-2.Eur. J. Cancer,27: 1014–1016, 1991.
18.
MoyM.P., HolmesE.C., GolubSM.: Depression of NK cytotoxic activity in lymphocytes infiltrating human pulmonary tumors.Cancer Res.45: 57–60, 1985.
19.
MarinoP., CugnoM., CoriP., RostiA., FrontiniL., CicardiM.: Increased levels of soluble interleukin-2 receptors in serum of patients with lung cancer.Br. J. Cancer,61: 434–435, 1990.
20.
PetersenJ.V., TvedeN., DiamantM., KjeruffA.A., SorensenH.R., AndersenV.: Soluble interleukin-2 receptor and soluble CD8 antigen levels in serum from patients with non resectable lung cancer.Cancer Immunol. Immunother.,33: 121–127, 1991.
21.
PisaniR.J., KrcoC.J., WoldL.E., MckeanD.J.: Lymphokine-activated kller (LAK) cell activity in tumor-infiltrating lymphocytes from non small cell lung cancer.Am. J. Clin. Pathol.,92: 435–446, 1989.
22.
PizzoloG., ChilosiM., SemenzatoG.: The soluble interleukin-2 receptor in haematological disorders.Br. J. Haematol.,67: 377–379, 1987.
23.
PoulakisN., SarandakouB.S.C., RizosD., PhocasI., Konto-zoglouT., PolyzogopoulosD.: Soluble interleukin-2 receptors and other markers in primary lung cancer.Cancer,68: 1045–1049, 1991.
RichardsJ.M., MickR., LattaJ.M., DalyK., RatainM.J., VardimanJ.V., GolombH.M.: Serum soluble interleukin-2 receptor is associated with clinical and pathological disease status in hairy cell leukemia.Blood,76: 1941–1945, 1990.
26.
RobinsonP., PinkstonP., CrystalRG.: Natural killer cells are present in the normal lung but are functionally impotent.J. Clin. Invest.,74: 942–950, 1984.
27.
RubinL.A., NelsonD.: The soluble interleukin-2 receptor: biology, function and clinical application.Ann. Intern. Med.,113: 619–627, 1990.
28.
SiziopikouK.P., HarrisJ.E., CaseyL., NawasY., BraunD.P.: Impaired tumoricidal function of alveolar macrophages from patients with non small cell lung cancer.Cancer,68: 1035–1044, 1991.
StarenE.D., EconomonS.G., HarrisJ.E., BraunD.P.: Lym-phokine-activated killer cell induction in tumor-infiltrating leukocytes from colon cancer patients.Cancer,64; 2238–2242, 1989.
31.
TisiE., LissoniP., AngeliM., ArrigoniC., CornoE., CassinaE., BallabioD., BenentiC., BarniS., TanciniG.: Postoperative increase in soluble interleukin-2 receptor serum levels as predictor for early recurrence in non small cell lung carcinoma.Cancer,69: 2458–2462, 1992.
32.
UchidaA., KariyaY., OkamotoN., SugieK., FujimotoT., YagitaM.: Prediction of postoperative clinical course by autologous tumor killing activity in lung cancer patients.J. Natl. Cancer Inst.,82: 1697–1701, 1990.
33.
VaccaA., Di StefanoR., FrassanitoA., IodiceG., DammaccoF.: A disturbance of the IL-2/IL-2 R receptor system parallels the activity of multiple myeloma.Clin. Exp. Immunol.,84: 429–434, 1991.
34.
VankyF., PeterffyL., BookK., WillemsJ., KleinE., KleinG.: Correlation between lymphocyte-mediated auto-tumor reactivities and the clinical course: evaluation of 69 patients with lung carcinoma.Cancer Immunol. Immunother.,16: 1722, 1983.
35.
VialeM., FerriniS., SerraroS.: Peripheral blood and tumor infiltrating lymphocytes in non small cell lung cancer: analysis at the population and clonal level.Tumori,5: 488–494, 1990.
36.
VitoloD., ZerbeT., KanbourA., DahlC., HebermanR.B., WhitesideT.L.: Expression of m-RNA for cytokine in tumor-infiltrating mononuclear cells in ovarian adenocarcinoma and invasive breast cancer.Int. J. Cancer,51: 573–580, 1992.
37.
VitoloD., KanbourA., JohnsonJ.T., HerbermanR.B., WhitesideT.L.: In situ hybridisation for cytokine gene transcripts in the solid tumour microenvironment.Eur. J. Cancer,3: 371–377, 1993.
38.
WagnerD.K., KiwanuraJ., EdwardsB.K., RubinL., NelsonD.L., MagrathJ.T.: Soluble intereleukin-2 receptor levels in patients with undifferentiated and lymphoblastic lymphomas: correlation with survival.J. Clin. Oncol.,5: 1282–1269, 1987.
39.
WaldmannT.: The IL-2/IL-2 receptor system: a target for rational immune intervention.Immunol. Today,14: 264–270, 1993.
40.
WeidmannE., SacchiM., PlaisanceS., HeoD.S., YasamuraS., LinW.C., JohnsonJ.T., HebermanR.B., AzzaroneB., WhitesideT.L.: Receptors for interleukin-2 on human squamous cell carcinoma cell lines and tumor in situ.Cancer Res.,52: 5693–5670, 1992.
41.
WeisslerJ.C., LipscombM.F., LemV.M., JowesG.B.: Tumor killing by human alveolar macrophages and blood monocuytes. Decreased cytotoxicity of human alveolar macrophages.Am. Rev. Respir. Dis.,134: 532–537, 1986.
42.
YamaguchiK., NishimuraY., KiyokawaT., MatsuzakiH., IshuT., KubotaK., KawakaraM., FuruseK., YoshinagaT., KinuwakiE., TakatsukiK.: Elevated serum levels of soluble interleukin-2 receptors in small cell lung cancer.J. Lab. Clin. Med.,116: 457–461, 1990.
43.
YasamuraS., WeidmannE., HirabayashiH., HebermanR.B., WhitesideT.L.: Characterization of functional interleukin-2 receptors of human solid tumors.Proc. Ann. Meet. Assoc. Cancer Res.,33: A290, 1992.
