文章(zhang)來源：
2015年ASCO年會于5月29日(ri)—6月2日(ri)在美(mei)國芝加(jia)哥召(zhao)開。5月30日(ri)下午消(xiao)化系統(tong)（結(jie)直腸）腫瘤口(kou)頭(tou)報告專場上，摘要(yao)號為(wei)3506的(de)(de)一(yi)項研究利用結(jie)直腸癌綜合(he)分子(zi)特征揭露了(le)免疫細胞浸潤的(de)(de)基因組預測。醫脈(mo)通整(zheng)理如(ru)下：
結(jie)直腸癌(ai)（CRC）是一種在(zai)復雜的(de)(de)微(wei)環(huan)境中(zhong)起病與(yu)進展(zhan)的(de)(de)分子(zi)異(yi)質性(xing)(xing)疾病。腫(zhong)瘤免疫細胞的(de)(de)浸潤已(yi)被證實與(yu)CRC特異(yi)性(xing)(xing)和總生存率的(de)(de)提高相關(guan)。然而(er)，CRC決定(ding)免疫浸潤數量(liang)與(yu)類型的(de)(de)基因組特征(zheng)在(zai)很(hen)大程度上尚未明確。
研究方法：
研(yan)(yan)(yan)究(jiu)人(ren)員從兩組(zu)大(da)型前瞻性(xing)隊列研(yan)(yan)(yan)究(jiu)（護(hu)士健康研(yan)(yan)(yan)究(jiu)和(he)(he)醫務(wu)人(ren)員追蹤研(yan)(yan)(yan)究(jiu)）中(zhong)選取了(le)689例原(yuan)發結直腸癌患(huan)者(zhe)（pts）進行了(le)全基(ji)因組(zu)測序和(he)(he)微(wei)衛星不穩定(ding)性(xing)（MSI）分析(xi)(xi)。用(yong)免(mian)疫(yi)(yi)組(zu)織化的(de)(de)方法標記了(le)免(mian)疫(yi)(yi)浸(jin)潤(run)的(de)(de)特征（瘤(liu)周(zhou)，瘤(liu)內腺(xian)體周(zhou)圍，Crohn''s狀，腫瘤(liu)浸(jin)潤(run)，和(he)(he)總淋巴細(xi)胞評分），同時對T細(xi)胞亞群（CD3+，CD8+，CD45RO+，FoxP3+）進行了(le)組(zu)織微(wei)陣列成像分析(xi)(xi)。他們利用(yong)一種新(xin)的(de)(de)計(ji)算途(tu)徑來計(ji)算腫瘤(liu)新(xin)抗(kang)原(yuan)負荷（由(you)體細(xi)胞突變產生的(de)(de)多(duo)肽，被免(mian)疫(yi)(yi)系統識別為異物），隨后將腫瘤(liu)新(xin)抗(kang)原(yuan)負荷與(yu)上述免(mian)疫(yi)(yi)變量和(he)(he)患(huan)者(zhe)生存(cun)相關(guan)聯。
研究結果：
相(xiang)較于微(wei)衛星(xing)穩(wen)定腫(zhong)瘤，微(wei)衛星(xing)高(gao)度不穩(wen)定的(de)腫(zhong)瘤明顯(xian)會(hui)表達更(geng)多(duo)的(de)新(xin)(xin)抗原(yuan)(yuan)(yuan)（P＜2e-16）。在原(yuan)(yuan)(yuan)發結直腸(chang)癌患者(zhe)中，腫(zhong)瘤新(xin)(xin)抗原(yuan)(yuan)(yuan)負荷與(yu)總(zong)淋(lin)巴細(xi)(xi)胞評分（P=4.9e-9）和(he)腫(zhong)瘤浸潤淋(lin)巴細(xi)(xi)胞（P=1.6e-15）顯(xian)著相(xiang)關。在T細(xi)(xi)胞亞群的(de)分析中，腫(zhong)瘤新(xin)(xin)抗原(yuan)(yuan)(yuan)負荷僅與(yu)CD45RO+ T細(xi)(xi)胞亞群（P=0.0003）顯(xian)著相(xiang)關。腫(zhong)瘤新(xin)(xin)抗原(yuan)(yuan)(yuan)負荷越高(gao)預示著CRC特異性和(he)總(zong)生(sheng)存(cun)率更(geng)高(gao)（分別為P=0.014，P=0.048）。
結論：
本項(xiang)大型(xing)前瞻性CRC分(fen)子特征(zheng)的(de)研究(jiu)顯示(shi)，腫瘤(liu)新抗原負荷預示(shi)著(zhu)更多的(de)腫瘤(liu)浸潤(run)淋巴細(xi)胞(bao)和記憶性T細(xi)胞(bao)浸潤(run)，可(ke)作(zuo)為CRC患者生存的(de)新型(xing)基因組預測指標。本研究(jiu)將腫瘤(liu)基因組學與特定免疫(yi)反應元素相關(guan)聯，對以后CRC的(de)治療決策有一(yi)定的(de)影響。
會議專(zhuan)題(ti)》》》2015年ASCO年會專(zhuan)題(ti)報道
閱讀摘(zhai)要原文(wen)：
Comprehensive molecular characterization of colorectal cancer reveals genomic predictors of immune cell infiltrates.（Abstract 3505）
Authors：Marios Giannakis, Sachet Shukla，et al.
Session Type：Oral Abstract Session
Background：Colorectal cancer (CRC) is a molecularly heterogeneous disease that arises and progresses in the context of a complex microenvironment. Tumor immune cell infiltrates have been shown to be associated with an improved CRC-specific and overall survival. However, the genomic features of CRC that determine the number and types of immune infiltrates remain largely uncharacterized.
Methods：We performed Whole Exome Sequencing and microsatellite instability (MSI) analysis on primary CRCs from 689 patients (pts) identified from two large prospective cohorts, the Nurses’ Health Study and the Health Professionals Follow-Up Study. We also immunohistochemically characterized the immune infiltrate (peritumoral, intratumoral periglandular, Crohn’s-like, tumor-infiltrating, and total lymphocyte score) and conducted tissue microarray imaging analysis for T-cell subsets (CD3+, CD8+, CD45RO+, FoxP3+). We utilized a novel computational pipeline to calculate tumor neoantigen load (peptides resulting from somatic mutations and recognized by the immune system as foreign) and subsequently correlated the tumor neoantigen load with the aforementioned immune variables and with pt survival.
Results：When compared to microsatellite-stable cancers, MSI-high tumors expressed significantly more neoantigens (P < 2e-16). Tumor neoantigen load significantly correlated with total lymphocytic score in the primary CRCs (P = 4.9e-9) and was most significantly associated with tumor infiltrating lymphocytes (P = 1.6e-15). Among T-cell subsets, tumor neoantigen load was only significantly associated with the CD45RO+ T-cell subset (P = 0.0003). Higher tumor neoantigen load predicted significantly improved CRC-specific and overall survival (P = 0.014 and P = 0.048, respectively).
Conclusions：In the large prospective study of molecularly characterized CRCs, tumor neoantigen load predicts greater tumor-infiltrating lymphocytes and memory T-cell infiltration and represents a novel genomic predictor of CRC survival. Our findings link tumor genomics to specific immune response elements and have implications for the therapeutic manipulation of the latter in CRC.