2018-08-012025-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/729287癌症免疫治療的發展已經進入臨床應用，而目前免疫調控節點抗體在腫瘤免疫調控，也由試驗階段開始運用於癌症患者的治療上。在我們先期研究中發現：在子宮內膜癌與子宮頸腺癌病患，癌細胞以寡核苷酸微陣列基因圖譜技術分析的基因群表現(Genome-wide scale oligonucleotide microarray techniques)有明顯差異，腫瘤微環境中的免疫調控亦不相同。對於子宮內膜癌與子宮頸腺癌基因群表現相關的免疫調控基因型表現機轉差異，仍需進一步釐清。本計畫延續先前我們的研究，在子宮內膜癌與子宮頸腺癌病患癌腫瘤浸潤淋巴球（tumor-infiltrating lymphocytes, TILs）中，CD4+CD25+ FoxP3+免疫調控細胞TREG的改變、與免疫調控CD8+T細胞對於細胞激素(cytokines)，與T細胞活化受體(T cell receptor, TCR)共同作用下的免疫調控毒殺作用的相關研究，針對目前癌症免疫治療的盲點，深入探討與TCR共同刺激活化分子與受體(TCR-related co-stimulatory molecules)的TREG細胞免疫調控。第一年計劃與第二年計劃主要延續並比對先前微陣列基因圖譜技術分析的子宮內膜癌與子宮頸腺癌基因群表現差異，並利用先前已建立的研究模式，由手術檢體分離癌腫瘤浸潤淋巴球與癌細胞，進行淋巴球細胞表面免疫抗原三重螢光染色技術與流式細胞儀(flowcytometry)，詳細分析癌腫瘤組織浸潤淋巴球與周邊血液細胞調控型TREG細胞免疫型別(immuno-phenotype) TCR共同刺激活化分子與受體在子宮內膜癌與子宮頸腺癌的差異性表現。第二年計劃將深入探討腫瘤細胞產生的免疫調控細胞激素基因與細胞激素群，對於調控型TREG細胞免疫反應型別現象進行相關性鏈結分析，並探討可能之原因。第三年計劃將進一步研究腫瘤微環境中TREG功能性變化的可能機轉，配合細胞激素對TREG受體影響之測定，對於子宮內膜癌與子宮頸腺癌免疫調控，深入探討在腫瘤存在的環境中，動態的子宮內膜癌與子宮頸腺癌病患TREG免疫調控差異。本研究預期能在子宮內膜癌與子宮頸腺癌免疫調控細胞表現型與功能性差異能有所突破，進一步應用於未來婦癌症臨床免疫治療的發展。Cancer immunotherapy is on-going in the clinical applications. Immunologic modulations with monoclonal antibodies have been utilized for treating a variety of cancer patients. In our previous unsupervised hierarchical clustering gene expression profiling studies, we find distinctive exemplifying inherent genetic and immunologic differences between human endometrial (EM) and endocervical (EC) adenocarcinomas, with selected immune regulating-subtypes. At present, little is known about the homeostasis and expression on tumor-infiltrating CD4+CD25+ FoxP3 regulatory T (TREG) cells in the human uterine cancer microenvironment. The effector functions of activated CD4+CD25+ FoxP3 TREG in cancer milieu are essential for elucidating the tumor immuno-pathogenesis. The present study will extend our previous findings and explore the kinetic regulations of tumor-infiltrating lymphocytes (TILs) with functional changes of FoxP3+ TREG cells in the human EM and EC adenocarcinomas. In the first year project, we will analyze the immuno-phenotypes and exploring the differential-expression of unsupervised hierarchical clustering gene profiles in fresh-isolated TILs by triple-color flow-cytometry. Our focus is concentrated on the expression of activation markers on CD3+CD25+ FoxP3+ TILs. In the second year project, we will investigate the homeostasis and functional lineage-expressions in CD4+ T cells, CD8+T cells to stratify the functional roles in correlated clustering gene profiles and cytokine receptors on immuno-sorted subsets of TREG. The kinetic activity with concordant expression of basic activation analyses of CD4+ T cells, CD8+ T cells, and NK-T cells will be illustrated between EM & EC cancer groups. In the third year project, we will explore the possible regulatory roles of cytokines on the kinetic activity with concordant expressions of certain TCR receptors on the TREG cells between. EM & EC cancer groups. The functional change of TREG cells will be evaluated and linked to the accumulated immuno-phenotypic functional assays in subjects with human EM and EC adenocarcinomas cancers. Our studies will shed new lights on the Immunologic modulations of cancer therapy in human corpus EM & EC cancers.