Pentheroudakis George, Raptou Georgia, Kotoula Vassiliki, Wirtz Ralph M, Vrettou Eleni, Karavasilis Vasilios, Gourgioti Georgia, Gakou Chryssa, Syrigos Konstantinos N, Bournakis Evangelos, Rallis Grigorios, Varthalitis Ioannis, Galani Eleni, Lazaridis Georgios, Papaxoinis George, Pectasides Dimitrios, Aravantinos Gerasimos, Makatsoris Thomas, Kalogeras Konstantine T, Fountzilas George
Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.
Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
PLoS One. 2015 May 13;10(5):e0124612. doi: 10.1371/journal.pone.0124612. eCollection 2015.
Although host immune response is an emerging prognostic factor for colorectal cancer, there is no consensus on the optimal methodology, surrogate markers or tissue for study.
Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour, invasive margin and adjacent normal mucosa.
Lymphocytic infiltration, deficient MMR (10.9%), KRAS (40.7%) and BRAF (4.9%) mutations or single mRNA gene expression were not prognostic. Tumour ESR1 gene expression (Hazard Ratio [HR] for relapse 2.33, 95% CI 1.35-4.02; HR for death 1.74, 95% CI 1.02-2.97) and absence of necrosis (HR for relapse 1.71, 95% CI 1.05-2.71; HR for death 1.98, 95% CI 1.14-3.43) were adverse prognostic features. We used CD3Z and CD8 expression in order to devise the mRNA-based Immune Score (mIS) and proceeded to partitioning analysis in 267 patients, with age, stage, tumour site (Right vs Left CRC), KRAS mutation and tumour mIS as input factors. Only in patients with stage III right-sided colon cancer, a low immune response was associated with inferior disease-free survival (mIS-low, HR for relapse 2.28, 95% CI 1.05-8.02). No prognostic significance was seen for tumour mIS in any other stage or site of CRC, or for a similar mIS score derived from adjacent normal mucosa. Independent adverse prognostic significance was retained in multivariable analysis for absence of necrosis, tumour ESR1 expression in all patients and low tumour mIS in stage III right-sided CRC.
In localised CRC, mRNA-based CD3Z/CD8 profiling of tumour immune response may have stage, site and tissue-specific prognostic significance, along with ESR1 expression.
ANZCTR.org.au ACTRN12610000509066.
尽管宿主免疫反应是结直肠癌一个新出现的预后因素，但在最佳研究方法、替代标志物或研究组织方面尚无共识。
前瞻性收集了344例接受辅助化疗的II/III期结直肠癌（CRC）患者的肿瘤组织块。通过qRT-qPCR研究了肿瘤中心、浸润边缘及相邻正常黏膜的组织微阵列（TMA）芯块中全切片淋巴细胞浸润情况以及CD3Z、CD8、CD4、CXCL9、CXCL13、IGHM、FOXP3、SNAI2和ESR1的mRNA表达。
淋巴细胞浸润、错配修复缺陷（10.9%）、KRAS（40.7%）和BRAF（4.9%）突变或单个mRNA基因表达均无预后意义。肿瘤ESR1基因表达（复发风险比[HR] 2.33，95%可信区间1.35 - 4.02；死亡HR 1.74，95%可信区间1.02 - 2.97）和无坏死（复发HR 1.71，95%可信区间1.05 - 2.71；死亡HR 1.98，95%可信区间1.14 - 3.43）是不良预后特征。我们利用CD3Z和CD8表达设计了基于mRNA的免疫评分（mIS），并对267例患者进行了分层分析，将年龄、分期、肿瘤部位（右半结肠癌与左半结肠癌）、KRAS突变和肿瘤mIS作为输入因素。仅在III期右半结肠癌患者中，低免疫反应与较差的无病生存期相关（mIS低，复发HR 2.28，95%可信区间1.05 - 8.02）。在CRC的任何其他分期或部位，肿瘤mIS或来自相邻正常黏膜的类似mIS评分均无预后意义。在多变量分析中，无坏死、所有患者的肿瘤ESR1表达以及III期右半结肠癌的低肿瘤mIS仍保留独立的不良预后意义。
在局限性CRC中，基于mRNA的肿瘤免疫反应CD3Z/CD8分析可能具有分期、部位和组织特异性的预后意义，以及ESR1表达。
ANZCTR.org.au ACTRN12610000509066。
