Indoleamine 2,3-Dioxygenase Expression In Esophageal Squamous Cell Carcinoma

Background and Objective Esophageal cancer including squamous cell carcinoma(ESCC)and adenocarcinoma has been considered as a highly aggressive lethal malignancy worldwide.During the last three decades,the long-term survival rate for patients with ESCC has not improved substantially,and the prognosis of ESCC remains among the worst sites for all cancers with respect to survival.The studies have clarified that the growth,invasiveness and metastasis of human tumors are not only determined by the tumor cells,but also by their surrounding stromal cells.It has been demonstrated that stromal cells can be beneficial to the cancer cells by releasing growth factors,immune regulating molecules,formation of new vascular(angiogenesis)and remodeling enzymes.Indoleamine 2,3-dioxygenase(IDO),an enzyme that degrades the essential amino acid l-tryptophan along the kynurenine pathway,has attracted considerable attention as a novel immunosuppressive factor in various types of human cancers.Increased synthesis of IDO protein may suppress host anti-tumor immunity and then contribute to cancer cell escape from attack by the host immune system.It has been well shown that the process of ESCC carcinogenesis will result in a reactive stromal response that plays a critical role in promoting the cancer cell growth and progression of ESCC.Indeed,we have previously demonstrated a strong reactive stromal response observed in the ESCC tumor microenvironment,which include the significant activation of tumor-associated fibroblasts(TAFs),increased formation of microvessels and production of proinflammatory cytokines.A remarkable stromal response has been found in vary types of human cancers including ESCC,in which highly expressed IDO is found.We,therefore,hypothesize that reactive TAF response and endothelial cells of microvessels might contribute to the orchestrating of immunosuppressive microenvironment by releasing of IDO in the ESCC tumor stroma.In this study,we therefore investigated the contribution of TAFs and endothelial cells of micro vessels for IDO expression in the ESCC tumor microenvironment.Materials and Methods The research was conducted on a group of 50 curative surgically resected tumor tissue paraffin blocksfrom ESCC patients and ten adjacent non-tumor esophageal tissues.Immunohistochemical examinationof TAFs,microvessels and IDO in ESCC tumor stroma.Double IHCs to define the expression of IDO and proliferation activity in stromal TAFs and microvessels.Results 1.SMA-alpha positive TAFs can be observed in in ESCC tumor stroma.SMA-alpha positive TAFs were observed in the whole tumor stroma but were particularly dense in the stromal region between tumor masses as compared with the controls.When the density of SMA-alpha positive TAFs was graded,the grading scores were greatly increased within the ESCC stroma relative to the controls.2.The CD34 IHC analysis showed that high density of MVD were observed in the ESCC tumor stroma relative to the controls,the counting data confirmed an significant increased MVD in the ESCC stroma.3.Increased IDO expression was observed in the ESCC tumor stroma relative to the controls.From a morphological view,many IDO positive cells present in the ESCC tumor stroma were likely TAFs and microvessels.The counting data confirmed a significant increased IDO positive TAFsand IDO positive MVD in the ESCC tumor stroma.4.The proliferation activity of reactive TAFs and microvessels in the ESCC tumor stroma was evaluated with double IHCs.The double IHC results showed that the proliferation activity labelled by PCNA immunoreactivity was frequently observed in SMA-alpha positive TAFs and CD34 positive endothelial cells of microvessels.Then we further examined the expression of IDO in TAFs and endothelial cells of microvessels in the ESCC tumor stroma with double IHCs.The results revealed that IDO immunoreactivity was frequently coexpresssed with SMA-alpha positive TAFs and CD34 positive endothelial cells of microvessels in the ESCC tumor stroma.Conclusion Here,we have shown that the TAFs and endothelial cells of microvessels are essential for the expression of IDO in ESCC.Therefore,we concluded that one of the mechanisms for tumor stroma in promoting ESCC growth and progression could be to release immunosuppressive factor IDO and then inhibits the host antitumor immunity.