The Alteration of T-Cell Heterogeneity and PD-L1 Colocalization During dMMR Colorectal Cancer Progression Defined by Multiplex Immunohistochemistry.
The Alteration of T-Cell Heterogeneity and PD-L1 Colocalization During dMMR Colorectal Cancer Progression Defined by Multiplex Immunohistochemistry.
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多重免疫组织化学定义的 dMMR 结直肠癌进展过程中 T 细胞异质性和 PD-L1 共定位的变化
DOI：
10.3389/fonc.2022.867658
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发表时间：
2022
影响因子：
4.7
通讯作者：
Huang, Dan
中科院分区：
文献类型：
--
作者：
Yan, Hongkai;Li, Yaqi;Wang, Xiaoyu;Qian, Juanjuan;Xu, Midie;Peng, Junjie;Huang, Dan
关键词：
免疫检查点抑制剂（ICI）正在迅速成为治疗错配修复缺陷（dMMR）结直肠癌（CRC）的关键工具。尽管有临床价值，但ICI的使用存在一些局限性。所有CRC中只有约15%具有dMMR状态，ICI的总体缓解率约为40%。ICI耐药的机制尚不清楚，其研究受到缺乏关于从早期到晚期dMMR CRC进展期间免疫微环境特征的信息的限制。我们使用多重免疫组化（mIHC）与两个面板，每个面板包含5个标记，同时分析免疫微环境成分的比例在59例晚期dMMR CRC和24例早期dMMR CRC患者。我们检测了上皮和间质区域的免疫细胞相关特征，并评估了这些免疫分子的预测价值。使用Student t检验、Mann-Whitney U检验、考克斯比例风险回归建模、单变量考克斯建模和Kaplan-Meier估计分析免疫细胞比例和存活数据。我们观察到晚期dMMR CRC中CD 8+细胞毒性T细胞（CD 8+）（p = 0.001）、CD 8+记忆T细胞（CD 8 + CD 45 RO+）（p = 0.032）和CD 4+调节性T细胞（CD 4 + FOXP 3+）（p = 0.011）的比例显著高于早期dMMR CRC。此外，与早期患者相比，晚期患者中具有PD-L1共定位的CD 3 + T细胞（CD 3 +PD-L1+）（p = 0.043）和具有PD-L1共定位的CD 8 + T细胞（CD 8 +PD-L1+）（p = 0.005）始终更多。我们的分析显示，高比例的CD 3 +PD-1+ T细胞是晚期患者总生存期（OS）[风险比（HR）= 9.6，p < 0.001]和无病生存期（DFS）（HR = 3.7，p = 0.010）的独立预后因素。大量的CD 8+细胞毒性T细胞和CD 8+记忆T细胞（通常代表适应性免疫系统的细胞毒性功能）和可能增强的抑制因子（如CD 4+调节性T细胞和PD-L1共定位T细胞）与dMMR CRC中免疫微环境从早期向晚期的转化相关。此外，CD 3 +PD-1+ T细胞是dMMR患者的预后因素。
Immune checkpoint inhibitors (ICIs) are quickly becoming key instruments in the treatment of mismatch repair-deficient (dMMR) colorectal cancers (CRCs). Despite their clinical value, ICIs have several limitations associated with their use. Only approximately 15% of all CRCs have a dMMR status, and the overall response rate of ICIs is approximately 40%. The mechanism of ICI resistance is not clear, and its study is limited by the lack of information available on the characterization of the immune microenvironment during the progression from early- to advanced-stage dMMR CRC. We used multiplex immunohistochemistry (mIHC) with two panels, each containing five markers, to simultaneously analyze the proportions of immune microenvironment constituents in 59 patients with advanced-stage dMMR CRC and 24 patients with early-stage dMMR CRC. We detected immune cell–associated signatures in the epithelial and stromal regions and evaluated the predictive value of these immune molecules. Student’s t-tests, Mann–Whitney U tests, Cox proportional hazards regression modeling, univariate Cox modeling, and Kaplan–Meier estimation were used to analyze immune cell proportions and survival data. We observed significantly higher proportions of CD8+ cytotoxic T cells (CD8+) (p = 0.001), CD8+ memory T cells (CD8+CD45RO+) (p = 0.032), and CD4+ regulatory T cells (CD4+FOXP3+) (p = 0.011) in the advanced-stage dMMR CRCs than in the early-stage dMMR CRCs. Furthermore, CD3+ T cells with PD-L1 colocalization (CD3+PD-L1+) (p = 0.043) and CD8+ T cells with PD-L1 colocalization (CD8+PD-L1+) (p = 0.005) were consistently more numerous in patients in the advanced stage than those in the early stage. Our analyses revealed that a high proportion of CD3+PD-1+ T cells was an independent prognostic factor of overall survival (OS) [hazard ratios (HR) = 9.6, p < 0.001] and disease-free survival (DFS) (HR = 3.7, p = 0.010) in patients in the advanced stage. High numbers of CD8+ cytotoxic T cells and CD8+ memory T cells, which usually represent a cytotoxic function of the adaptive immune system and possibly enhanced inhibition factors, such as CD4+ regulatory T cells and PD-L1 colocalized T cells, were associated with the transformation of the immune microenvironment from the early stage to the advanced stage in dMMR CRCs. Furthermore, CD3+PD-1+ T cells are a prognostic factor for patients with dMMR.
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影响因子：
29.4
作者：
Boland CR;Goel A
通讯作者：
Goel A
影响因子：
9.2
作者：
Fan A;Wang B;Wang X;Nie Y;Fan D;Zhao X;Lu Y
通讯作者：
Lu Y
影响因子：
7.5
作者：
Ge, Penglei;Wang, Weiwei;Wu, Yang
通讯作者：
Wu, Yang
DOI：
10.1126/science.aar3593
发表时间：
2018-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cristescu R;Mogg R;Ayers M;Albright A;Murphy E;Yearley J;Sher X;Liu XQ;Lu H;Nebozhyn M;Zhang C;Lunceford JK;Joe A;Cheng J;Webber AL;Ibrahim N;Plimack ER;Ott PA;Seiwert TY;Ribas A;McClanahan TK;Tomassini JE;Loboda A;Kaufman D
通讯作者：
Kaufman D
影响因子：
50.3
作者：
Lu, Changzheng;Guan, Junhong;Lu, Steve;Jin, Qihuang;Rousseau, Benoit;Lu, Tianshi;Stephens, Dennis;Zhang, Hongyi;Zhu, Jiankun;Yang, Mingming;Ren, Zhenhua;Liang, Yong;Liu, Zhida;Han, Chuanhui;Liu, Longchao;Cao, Xuezhi;Zhang, Anli;Qiao, Jian;Batten, Kimberly;Chen, Mingyi;Castrillon, Diego H.;Wang, Tao;Li, Bo;Diaz, Luis A., Jr.;Li, Guo-Min;Fu, Yang-Xin
通讯作者：
Fu, Yang-Xin