| As one of the most commonly diagnosed disease,cervical cancer is severely harmful to women's health.In recent years,preoperative neoadjuvant chemotherapy emerges as a valuable treatment for patients with locally advanced cervical cancer and it has cause more and more attention from gynecologists.The response to chemotherapy is different between individuals.Only patients who are sensitive to chemotherapy can benefit from NAC.At present,the response to chemotherapy is valued by vaginal pelvic examination and transvaginal ultrasonography and thus,the accuracy is not guaranteed due to many subjective factors.Histological response by morhphlogic criteria has been used in several cancers and the degrees of tumor regression are correlated with the prognosis of several types of cancers.It is very important to predict the chemosensitivity before NACT,while few markers could be used to predict the sensitivity of NACT so far.Recnt evidences have shown that CD8+ cytotoxic T cells and FOXP3+ regulatory T cells in the complex immune network in the local microenvironment have great influences on the sensitivity of chemotherapy.To start from tumor microenvironment,we explore the relationship between local immune status and chemotherapy and provide new clues for individualized treatment.The progression of cervical cancer is associated with the abnormity of immunologic system.Recently,Myeloid-Derived Suppressor Cells(MDSCs)as a kind of unique cell populations that can regulate the immune response,have received much attention.The accumulation of MDSCs in peripheral blood is closely associated with disease progression in many tumors.The aim of the study is to establish a new histological grading criteria for cervical cancer patients after NACT and to investigete the potential immune factors asscociated with disease progression in the tumor microenvironment and peripheral blood.Part? Prognostic value of pathological grading criteria in cervical cancer patients with NACTObjective:To establish a histological evaluation criterion,that may be useful for predicting survival in cervical cancer patients after NACT.Methods:A novel 4-tiered pathological grading criterion including optimal response(Grade 1),viable tumor cells occupying<2/3(Grade 2)or>2/3(Grade 3)of the tumor bed area,and cases with extra-cervical deposit(Grade 4)was developed.190 patients with bulky FIGO stage Ib2 and Ila cervical squamous cell carcinoma were included in this classification.Cox proportional hazards models were fitted for multivariate analysis.Results:1.All patients with<2/3 viable tumor cells had longer periods of PFS.Moreover,in patients without extra-cervical deposits,both PFS and OS were longer in patients with<2/3 viable tumor cells.While in patients with extra-cervical deposits,the volume of the viable tumor cells had no effect on survival.2.There were statistically significant differences in PFS and OS across all pathological grades by Kaplan-Meier analysis with Log-rank test.Multivariate analyses using Cox proportional hazard model showed that the pathologic grading criterion was the only independent predictor for both PFS and OS.3.Both PFS and OS of patients with<2/3 viable tumor cells were significantly better than patients with>2/3 viable tumor cells,or those with extra-cervical deposits.Conclusion:1.The 4-tiered pathological grading criterion is the independent prognostic factor for both PFS and OS.2.Patients with<2/3 viable tumor cells may together with patients with optimal response to NAC and have an improved outcomes.Part II The significance of the expression of local immunological cells before and after NACT for cervical cancer patientsObjective:To assess the effection of NACT on CD8+ and FOXP3+ cells in tumor microenvironment;To investigate the prognostic value of both CD8+ and FOXP3+ cells in the chemotherapy sensitivity and cervical cancer prognosis.Methods:137 cases of bulky FIGO stage Ib2-?a cervical cancer patients with complete clinical follow-up data were included in this study.The infiltration of CD8+ and FOXP3+ cells was assessed by immunohistochemistry in different areas(within the tumor and tissues surrounding tumor)before and after chemotherapy.Both sensitivity to chemotherapy and the prognosis of cervical cancer patients was evaluated through univariate and multivariate analysis.Results:1.Before chemotherapy,decreased infiltration of CD8+ cells within tumor was significantly associated with lympho node metastasis.2.Before chemotherapy,the infiltration of FOXP3+ cells within tumor was independent predictor for sensitivity to chemotherapy.3.The number of CD8+ cells was unchangable before and after chemotherapy,while great decreased FOXP3+ cells was observed after chemotherapy.After chemotherapy,decreased infiltraton of FOXP3+ cells around tumor was associated with pathological optimal response to chemotherapy.4.Univariate survival analysis showed that the number of intratumoral CD8 cells after chemotherapy was positively correlated with PFS and OS,while the number of peritumoral FOXP3 cells after chemotherapy was negatively associated with OS and PFS.5.Multivariate survival analysis showed that the increased raito of intratumoral CD8+ cells/peritumoral FOXP3+ cells after chemotherapy was the independent predictor for improved OS and PFS.Conclusion:1.CD8+ cells are unchangable before and after chemotherapy,while FOXP3+ cells are great decreased after chemotherapy.After chemotherapy,decreased infiltraton of FOXP3+ cells around tumor is associated with pathological optimal response to chemotherapy.2.The infiltration of peritumoral FOXP3+ cells before chemotherapy is an independent predictor of sensitivity to chemotherapy.3.The raito of intratumoral CD8+ cells/peritumoral FOXP3+ cells after chemotherapy is the independent predictor of OS and PFS for cervial cancer patients with NACT.Part ? Detection and Clinical Significance of the circulating MDSCs in patients with cervical cancerObjective:To investigate the presence and definite phenotype of circulating MDSCs in patients with cervical cancer;To analyze related cytokines and immunosuppressive function of MDSCs in order to provide a new idea for further study on the immune status and prognosis of patients.Methods:Whole bloods were obtained from cervical cancer patients(n=51)and healthy donors(n=15).The frequency of MDSCs subtypes defined as HLADR-Lin-CD11b+CD33+ CD15+ CD14-GrMDSCs or CD14+ HLADR-/low MoMDSCs was detected by flow cytometry.CD8+ and FOXP3+ cells were detected in the tumor microenvironment through IHC.Certain MDSCs subtype relevant with clinicalpathological factors and chemosensitivity was further analysed for pSTAT3 and CFSE-labeled autologous T cell proliferation.Results:1.The frequency of circulating HLADR-Lin-CD11b+ CD33+ CD15+ CD14-GrMDSCs was positively correlated with clinical cancer stage and there was a increasing trend of GrMDSCs levels from early stage to advanced stage.However,the precentage of CD14+ HLADR-/lowMoMDSCs increased only in patients with advanced cervical cancer.2.The frequency of GrMDSCs was closely related with the high risk factors of tumor progression,such as lympho node metastasis and deep stromal invasion and was negatively associated with the expression of CD8+ cells in tumor microenvironments.3.GrMDSCs in cervical cancer showed elevated pSTAT3 levels and had the capacity to inhibit the proliferation of autologous T cells in vitro.Conclusion:1.High levels of MDSCs are explored in the peripheral blood of cervical cancer patients.In early stage,GrMDSCs are the main subtype,while both GrMDSCs and MoMDSCs are present in late stage.2.GrMDSCs in cervical cancer patients have high levels of pSTAT3,strong inhibition activity,and are associated with high risk factors of tumor progression. |
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