本文關(guān)鍵詞： 直腸癌 新輔助同步放化療 免疫微環(huán)境 巨噬細(xì)胞 腫瘤浸潤(rùn)淋巴細(xì)胞 治療反應(yīng) 預(yù)后　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類型：學(xué)位論文

【摘要】：研究目的術(shù)前的新輔助同步放化療(neoadjuvant chemoradiotherapy,NCRT)是局部進(jìn)展期直腸癌的國(guó)際上標(biāo)準(zhǔn)首先治療方案。但不同個(gè)體對(duì)于NCRT的療效有顯著差別;臨床上還觀察到,一部分患者在接受過(guò)新輔助治療后,其術(shù)后的復(fù)發(fā)轉(zhuǎn)移模式發(fā)生改變,肺轉(zhuǎn)移成為主要的轉(zhuǎn)移部位。這提示NCRT可能使得腫瘤本身生物學(xué)行為發(fā)生改變,甚至腫瘤的免疫微環(huán)境向著有利于腫瘤細(xì)胞侵襲和轉(zhuǎn)移的方向改變。本研究擬通過(guò)分析新輔助放化療后腫瘤細(xì)胞及免疫微環(huán)境的變化及與療效、預(yù)后的相關(guān)性,鑒定與治療反應(yīng)相關(guān)的高頻突變,為發(fā)展新的聯(lián)合治療策略和建立腫瘤治療預(yù)后診斷的分子標(biāo)記提供分子標(biāo)記物。材料與方法本研究回顧性收集及分析在1994-2013年間,在中國(guó)醫(yī)學(xué)科學(xué)院腫瘤醫(yī)院接受新輔助長(zhǎng)程同步放化療及根治性手術(shù)切除的局部進(jìn)展期中-低位直腸癌患者的臨床病理資料,觀察其組織病理學(xué)的變化,分別對(duì)腫瘤細(xì)胞表面與上皮間質(zhì)轉(zhuǎn)化(EMT)、腫瘤干細(xì)胞(CSC)、腫瘤浸潤(rùn)淋巴細(xì)胞(TIL)、腫瘤相關(guān)巨噬細(xì)胞(TAM)、免疫卡控點(diǎn)(immuneblockade)和若干細(xì)胞因子的相關(guān)標(biāo)記進(jìn)行免疫組化染色,比較免疫微環(huán)境中各組分的變化,將其分別與病人的臨床因素、治療反應(yīng)及預(yù)后進(jìn)行相關(guān)性及生存分析。結(jié)果本研究共納入329例患者,中位隨訪時(shí)間37.3個(gè)月。單因素分析發(fā)現(xiàn),ypT分期、ypN分期、腫瘤衰退分級(jí)(TRG)均與新輔助同步放化療患者DFS的顯著相關(guān)(P0.0001,P0.0001,P0.0001)。但在非 pCR 組(N=283)中,ypT 分期與患者的DFS無(wú)顯著相關(guān)性(P=0.2272),多因素分析發(fā)現(xiàn),ypN分期是唯一影響新輔助同步放化療后直腸癌患者DFS的獨(dú)立危險(xiǎn)因素,而ypT分期、TRG均未被證實(shí)為獨(dú)立預(yù)后因素。而將ypT分期和TRG的權(quán)重結(jié)合后的預(yù)后分組定義為M-TTRG分組,發(fā)現(xiàn)不同M-TTRG分組的3y-DFS分別為83.9%、68.8%、59.7%和33.3%(P0.0001)。進(jìn)一步的免疫組化分析顯示,與腫瘤衰退分級(jí)(TRG)相關(guān)的因素包括CD68+巨噬細(xì)胞的浸潤(rùn),CD3+、CD4、CD8+淋巴細(xì)胞的浸潤(rùn)、腫瘤細(xì)胞PD-L1的表達(dá)以及IL-10的分泌。生存分析結(jié)果顯示,在新輔助治療后腫瘤細(xì)胞高表達(dá)CD133(P=0.0271)、ALDH1(P=0.0206),CD163+TAM 高浸潤(rùn)(P=0.0206),CD3+(P=0.0150)、CD8+(P=0.0011)TIL低浸潤(rùn)以及腫瘤間質(zhì)中α-SMA高表達(dá)(P=0.0022)與術(shù)后DFS縮短顯著相關(guān)。結(jié)論在新輔助治療后,ypT不能夠準(zhǔn)確預(yù)測(cè)直腸癌患者的預(yù)后,TRG可以對(duì)ypT分期進(jìn)行修正及改良,改良后的TNM分期可以很好的預(yù)測(cè)患者的DFS。腫瘤免疫微環(huán)境中的各組分在新輔助治療后均發(fā)生顯著性的改變,腫瘤細(xì)胞高表達(dá)干細(xì)胞特征標(biāo)記或高浸潤(rùn)的M2型TAM、低浸潤(rùn)總淋巴細(xì)胞和CTL的患者,術(shù)后更容易出現(xiàn)復(fù)發(fā)和轉(zhuǎn)移。
[Abstract]:Objective to study neoadjuvant chemoradiotherapy in neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy and neoadjuvant before operation. NCRT is the international standard for the treatment of locally advanced rectal cancer, but there are significant differences between individuals in the efficacy of NCRT. It was also observed that the recurrence and metastasis pattern of some patients changed after neoadjuvant therapy. Lung metastasis is the main metastatic site. This suggests that NCRT may change the biological behavior of the tumor itself. Even the immune microenvironment of tumor changes in favor of tumor cell invasion and metastasis. This study aims to analyze the changes of tumor cells and immune microenvironment after neoadjuvant radiotherapy and chemotherapy and the relationship between tumor cell and prognosis. High frequency mutations associated with therapeutic response were identified. Materials and methods the materials and methods of this study were collected and analyzed retrospectively from 1994 to 2013. The clinicopathological data and histopathological changes of patients with advanced and low rectal cancer received neoadjuvant long term radiotherapy and chemotherapy and radical resection were observed at the Cancer Hospital of the Chinese Academy of Medical Sciences. The tumor cell surface and epithelial mesenchymal transformation (EMT), tumor stem cell (CSCC), tumor infiltrating lymphocytes (TILL) and tumor associated macrophage (TAM) were studied. Immunohistochemical staining was used to compare the changes of each component in immune microenvironment, and to compare the changes of each component with the clinical factors of the patients. Results 329 patients were included in this study with a median follow-up time of 37.3 months. The DFS of neoadjuvant radiotherapy and chemotherapy patients were significantly correlated with tumor decline grade (P0. 0001) and neoadjuvant chemotherapy (P0. 0001). P 0.0001, but in non-#en0# group (n = 283), there was no significant correlation between the stage of PypT and the DFS of the patients (P = 0.2272). The multivariate analysis showed that there was no significant correlation between the stage and the DFS of the patients. YpN staging was the only independent risk factor for DFS in patients with neoadjuvant concurrent radiotherapy and chemotherapy, while ypT staging. TRG was not proved to be an independent prognostic factor, and the prognostic group combined with ypT stage and TRG was defined as M-TTRG group. It was found that the 3y-DFS of different M-TTRG groups were 83.9% and 33.3% respectively. The factors associated with the decline of tumor grade include the infiltration of CD68 macrophages and the infiltration of CD3 / CD4 / CD8 cells. The expression of PD-L1 and the secretion of IL-10 in tumor cells. Survival analysis showed that the expression of CD133P was highly expressed in tumor cells after neoadjuvant therapy. The CD163 TAM of ALDH1 / P0. 0206 TAM was highly infiltrated (P0. 0206 and CD3 / P0. 0150). The low infiltration of CD8 and the high expression of 偽 -SMA in the stroma were significantly associated with the shortening of DFS after neoadjuvant therapy. Conclusion\\\; YpT can not accurately predict the prognosis of rectal cancer patients. YpT staging can be modified and modified by ypT. The modified TNM staging can well predict the changes of each component in tumor immune microenvironment after neoadjuvant therapy. Patients with high expression of stem cell characteristic markers or high infiltration of type M2 TAM, low infiltration of total lymphocytes and CTL were more prone to recurrence and metastasis after operation.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R735.37

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