RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:Chemoradiation-induced alteration of programmed death-ligand 1, CD8+ tumor-infiltrating lymphocytes and mucin expression in rectal cancer.
Chemoradiation-induced alteration of programmed death-ligand 1, CD8+ tumor-infiltrating lymphocytes and mucin expression in rectal cancer.
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nCRT 暴露与直肠腺癌患者 PD-L1 表达的差异无统计学意义,可能是由于样本量限制。需要进一步的机制研究和全面的免疫分析,以了解 nCRT 诱导的直肠癌免疫转变,并扩大检查点抑制剂在此背景下的适用性。
DNA损伤及由此产生的新抗原形成被认为是放疗与PD-1/PD-L1通路抑制协同诱导抗肿瘤免疫反应的机制。我们研究了直肠癌患者中新辅助放化疗(nCRT)诱导的CD8+TIL(肿瘤浸润淋巴细胞)、PD-L1和黏蛋白表达的变化。
收集了2008-2014年间接受切除术的直肠腺癌患者肿瘤样本,其中接受nCRT治疗者(n = 62)和未接受nCRT治疗者(n = 17)。切片用CD8和PD-L1抗体进行免疫组化染色。记录肿瘤、肿瘤交界处和背景直肠侧CD8+细胞的分布情况。使用图像分析确定CD8+淋巴细胞的密度。在肿瘤细胞(TC)、肿瘤间质(TS)和浸润前沿(IF)中手动计数PD-L1表达的百分比。黏蛋白表达确定为黏蛋白面积占整个肿瘤面积的百分比。
在nCRT标本中,7.6%(6/79)检测到TCs上PD-L1表达(p = 0.33),而非nCRT患者中无一例表达。两组间CD8+浸润性T淋巴细胞中位密度无显著差异。nCRT队列中黏蛋白表达显著更高(p = 0.02)。nCRT后较高的中性粒细胞与淋巴细胞比值(NLR)与较差预后相关(HR = 1.04,95% CI = 1.00-1.08)。
Tumor samples of rectal adenocarcinoma patients undergoing resection between 2008-2014 with ( n = 62) or without ( n = 17) nCRT treatment were collected. Sections were stained with CD8 and PD-L1 antibodies for immunohistochemistry. The prevalence of CD8+ cells was recorded in the tumor, interface tumor and background rectal side. Image analysis was used to determine the density of CD8+ lymphocytes. The percentage of PD-L1 expression was manually counted in tumor cells (TC), tumor stroma (TS) and the invasive front (IF). Mucin expression was determined as the percentage of the mucin area in the whole tumor area.
PD-L1 expression on TCs was identified in 7.6% (6/79) of nCRT specimens ( p = 0.33) and in none of the non-nCRT patients. Median densities of CD8+ infiltrating T lymphocytes did not differ significantly between the two groups. Mucin expression was significantly higher in the nCRT cohort ( p = 0.02). Higher neutrophil to lymphocytes ratio (NLR) after nCRT was associated with worse outcome (HR = 1.04, 95% CI = 1.00-1.08).
nCRT exposure was associated with a non-significant difference in PD-L1 expression in rectal adenocarcinoma patients, possibly due to sample size limitations. Further mechanistic investigations and comprehensive immune analysis are needed to understand nCRT-induced immunologic shift in rectal cancer and to expand the applicability of checkpoint inhibitors in this setting.
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