Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer
Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer
复制标题
DOI：
10.1016/j.ebiom.2020.102860
复制
发表时间：
2020-07-01
期刊：
影响因子：
11.1
通讯作者：
Ogino, Shuji
中科院分区：
文献类型：
--
作者：
Fujiyoshi, Kenji;Vayrynen, Juha P.;Ogino, Shuji
背景：肿瘤出芽和低分化簇（PDC）代表肿瘤侵袭的形式。我们假设t细胞密度（反映适应性抗肿瘤免疫）可能与结直肠癌的肿瘤出芽和PDC呈负相关。方法：利用两项美国范围内的915例结肠癌和直肠癌的前瞻性队列研究，采用多重免疫荧光结合机器学习算法，我们评估了CD3、CD4、CDS、CD45RO （PTPRC）和FOXP3在淋巴细胞中的共表达模式。采用国际肿瘤萌芽共识会议标准，通过数字病理学和图像分析对侵袭前沿的肿瘤萌芽和PDC进行量化。利用4420例结直肠癌病例的协变量数据，将逆概率加权（IPW）与多变量logistic回归分析相结合，评估t细胞亚群密度与肿瘤出芽和PDC之间的关系，同时调整因组织可用性和潜在混杂因素（包括微卫星不稳定状态）导致的选择偏差。结果：肿瘤出芽计数与CD3（+）和CD8（+）密度呈负相关[最低与最高：多变量优势比（OR）， 0.50；95%置信区间（CI）， 0.35-0.70；肿瘤上皮区CD3(+)CD8(+)CD45R0（+）细胞（最低vs最高：多变量OR， 0.44; 95% CI, 0.31-0.63； p趋势< 0.001）。在Cox回归分析中，肿瘤出芽水平与较高的结直肠癌特异性死亡率相关（多变量风险比，2.13;95% CI, 1.57-2.89； p趋势< 0.001）。PDC与t细胞亚群无显著相关性。解释：肿瘤上皮细胞和记忆细胞毒性T细胞密度与侵袭前沿的肿瘤出芽呈负相关，表明细胞毒性抗肿瘤免疫抑制肿瘤微侵袭。
Background: Tumour budding and poorly differentiated clusters (PDC) represent forms of tumour invasion. We hypothesised that T-cell densities (reflecting adaptive anti-tumour immunity) might be inversely associated with tumour budding and PDC in colorectal carcinoma.Methods: Utilising 915 colon and rectal carcinomas in two U.S.-wide prospective cohort studies, and multiplex immunofluorescence combined with machine learning algorithms, we assessed CD3, CD4, CDS, CD45RO (PTPRC), and FOXP3 co-expression patterns in lymphocytes. Tumour budding and PDC at invasive fronts were quantified by digital pathology and image analysis using the International tumour Budding Consensus Conference criteria. Using covariate data of 4,420 incident colorectal cancer cases, inverse probability weighting (IPW) was integrated with multivariable logistic regression analysis that assessed the association of T-cell subset densities with tumour budding and PDC while adjusting for selection bias due to tissue availability and potential confounders, including microsatellite instability status.Findings: Tumour budding counts were inversely associated with density of CD3(+)CD8(+) [lowest vs. highest: multivariable odds ratio (OR), 0.50; 95% confidence interval (CI), 0.35-0.70; P-trend < 0.001] and CD3(+)CD8(+)CD45R0(+) cells (lowest vs. highest: multivariable OR, 0.44; 95% CI, 0.31-0.63; P-trend < 0.001) in tumour epithelial region. Tumour budding levels were associated with higher colorectal cancer-specific mortality (multivariable hazard ratio, 2.13; 95% CI, 1.57-2.89; P-trend < 0.001) in Cox regression analysis. There were no significant associations of PDC with T-cell subsets.Interpretation: Tumour epithelial na ve and memory cytotoxic T cell densities are inversely associated with tumour budding at invasive fronts, suggesting that cytotoxic anti-tumour immunity suppresses tumour microinvasion.