Detection Of The Activity Of Indoleamine 2,3-dioxygenase In Serum In The Patients With Advanced Non-small Cell Lung Cancer And Its Clinical Implication

Background and Purpose: Lung cancer is the leading cause of cancer-related mortality worldwide.Non–small cell lung cancer(NSCLC)comprises approximately 85% of all lung cancer patients.Among patients with NSCLC,approximately 70% present with advanced stage at the time of diagnosis.Patients with locally advanced stage and good performance status can get eight months of disease-free survival after a series of anti-cancer treatments,such as chemotherapy,radiotherapy and surgical treatment.Although the median survival of patients with advanced NSCLC has prolonged at some level because the new generation of cytotoxic or molecular target drugs,the survival rates of the patients were not improved drastically.Recently,as the interaction between the malignant tumors and the human immune system as well as the mechanisms via which tumor cells escape from the immune surveillance becomes better understood,treatment of cancer has entered a new era of immune treatment.During the immune response,however,some of the transformed cancer cells employ several immune evasion strategies to generate an immunosuppressive microenvironment to overcome the immune response,resulting in tumor progression.The most important mechanism of immune tolerance by which cancer cells escape the immune system is that indoleamine 2,3-dioxygenase(IDO)expressed by cancer cells catalyzes the tryptophan(Trp)through the kynurenine(Kyn)metabolic pathway.The activity of IDO can be estimated by the ratio of kynurenine concentration and tryptophan concentration(Kyn/Trp ratio).T cells play a significant role in the immune response to cancer cells in the microenvironment,however,IDO diminish the local tryptophan which is an essential amino acid for T cells to proliferate.The decrease of local tryptophan can inhibit the growth of T cells and induce T cells apoptosis.Increased expression of IDO has been observed in wide range of types of human solid tumors as well as hematological malignancies.The studies found that IDO can promote tumor progression,develop resistance to cytotoxic drugs and correlates with poor prognosis of malignant tumors.The inhibitors of IDO,such as 1-methyl-tryptophan(1-MT),have shown remarkable ability to inhibit IDO activity in inhibiting cancer cells growth in animal models.The objective of our study was to clarify the correlations between the serum IDO activity and the progression of tumor;explore whether IDO activity can be a predictor of the responses to chemotherapy and the prognosis of patients with advanced NSCLC with the purpose of offering a new direction of evaluating the short-term and long-term effect and providing theoretical basis of improving the immunosuppression status of patients so as to improve the prognosis.Methods: The present study measured the serum tryptophan and kynurenine concentrations before and after two cycles of chemotherapy by high performance liquid chromatography(HPLC)and estimated the IDO activity in stage IIIB or IV NSCLC patients.Results: 1.The serum concentration of tryptophan(p<0.05),kynurenine(p<0.05)and IDO activity(p<0.05)are significantly high in patients with NSCLC compared to the controls.ROC curve analysis showed that serum IDO activity were of high diagnostic value for advanced NSCLC.With the sensibility at 71.4% and the specificity at 98.2%,and the area under a curve of 0.856 [95%CI(0.814~0.897)] illustrated that IDO activity is a reasonable diagnosis indicator for advanced NSCLC.2.Patients with lung adenocarcinoma had significantly lower concentration of tryptophan(p<0.05),higher IDO activity(p<0.05)than the patients with squamous cell carcinoma,the concentration of tryptophan did not reach statistical significance(p>0.05).When comparing patients with locally advanced disease,significant decreases in serum concentration of tryptophan(p<0.05),higher IDO activity(p<0.05)in patients with metastatic disease,the kynurenine concentration,which did not reach statistical significance(p>0.05).Patients with pleural effusion at the time of diagnosis had significantly higher IDO activity than the patients without pleural effusion (p<0.05).However,we did not find significance between the subgroups of other metastatic sites(p>0.05).3.We did not find significance between the concentrations of tryptophan,kynurenine and IDO activity and the subgroups of age,sex,KPS scale and smoking status(p>0.05).4.There was no significance between the pretreatment serum IDO activity and serum posttreatment IDO activity(p>0.05).A significant association was found between the pretreatment IDO activity as well as the rate of decline of IDO activity and the responses to chemotherapy(p<0.05).5.Patients with low IDO activity has a prolonged overall survival than the patients with high IDO activity(p<0.05).Long overall survival was also found in patients with high rate of the decline of IDO activity compared to the patients with low rate of the decline of IDO activity(p<0.05).Cox regression showed that age,pretreatment IDO activity,responses to chemotherapy and radiotherapy were the independent prognosis factors for patients with advanced NSCLC.Conclusion: IDO was abundantly expressed in patients with advanced NSCLC.IDO can protect the cancer cells from immune surveillance,promote cancer progression,induce resistance to chemotherapy,influence the responses to chemotherapy and the prognosis of patients with advanced NSCLC.