不同微卫星状态下胃癌中PD1/PDL1的表达及其与肿瘤微环境中浸润免疫细胞的相关性

Expression of PD1/PDL1 in gastric cancer at different microsatellite status and its correlation with infiltrating immune cells in the tumor microenvironment.

作者信息

Wang Yan-Li, Gong Yuehua, Lv Zhi, Li Liang, Yuan Yuan

机构信息

Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China.

Department of Medical Oncology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China.

出版信息

J Cancer. 2021 Jan 18;12(6):1698-1707. doi: 10.7150/jca.40500. eCollection 2021.

Abstract

The microsatellite status and tumor immune microenvironment have a remarkable influence on tumor immunotherapy. This study was performed to investigate programmed cell death protein 1/programmed death ligand 1 (PD1/PDL1) expression and their correlations with CD8+ T cell/CD68+ macrophage (CD68+ M) densities in gastric cancer (GC) at different microsatellite statuses. The expression of MLH1, PMS2, MSH2, and MSH6 was detected via immunohistochemistry (IHC) to determine the microsatellite status in 215 GC samples obtained from surgical resections. Furthermore, the expression of PD1, PDL1, CD8, and CD68 was detected in the samples via IHC, and the differences and correlations in GC at different microsatellite statuses were then analyzed. PDL1 expression in tumor cells was labeled as PDL1[T], while expression of PD1 and PDL1 in tumor-infiltrating immune cells was labeled as PD1 and PDL1, respectively. Kaplan-Meier analysis was used to evaluate the significance of PD1/PDL1 expression in determining overall survival. Multivariate Cox regression analysis was performed using SPSS software. P-values were determined using the log-rank test. Our results indicated that PD1, PDL1[T], and PDL1 positivity rates were 59%, 35%, and 57% in 46 microsatellite unstable (MSI) GCs and 45%, 22%, and 40% in 169 microsatellite stable (MSS) GCs, respectively. Compared with MSS GC, PD1, PDL1[T], and PDL1 expression was higher in MSI GC (P = 0.109, 0.090, and 0.044, respectively). Additionally, CD8+ T cell and CD68+ M densities were higher in MSI GC than in MSS GC (P = 0.537 and <0.001, respectively). Additionally, CD8+ T cell/CD68+ M densities were evaluated according to tumor center and invasion front. We found that PD1 expression was significantly correlated with CD8+ T cell density at the invasion front of the MSI GC (P = 0.031), whereas PDL1 expression was significantly correlated to high CD68+ M density in the tumor center and invasion front of MSS GC (P = 0.001 and 0.014, respectively). Survival analysis showed that patients with PD1-positive and PDL1[T]/PDL1-negative GC had better prognosis (P = 0.012, 0.005, and 0.022, respectively). Multivariate Cox survival analysis showed that PDL1[T] was an independent prognostic factor for GC. The results suggested that PD1/PDL1 expression and immune response varied at different microsatellite statuses in GC. PD1/PDL1 expression was correlated with CD8+ T cell/CD68+ M densities in GC at different microsatellite statuses, especially at the invasion front. The patients exhibiting high PD1/PDL1 expression or high CD8+ T cell/CD68+ M densities MSI GC might be potential beneficiaries of PD1/PDL1 immunotherapy.

摘要

微卫星状态和肿瘤免疫微环境对肿瘤免疫治疗有显著影响。本研究旨在探讨程序性细胞死亡蛋白1/程序性死亡配体1(PD1/PDL1)的表达及其与不同微卫星状态下胃癌(GC)中CD8+T细胞/CD68+巨噬细胞(CD68+M)密度的相关性。通过免疫组织化学(IHC)检测MLH1、PMS2、MSH2和MSH6的表达,以确定从手术切除获得的215例GC样本中的微卫星状态。此外,通过IHC检测样本中PD1、PDL1、CD8和CD68的表达,然后分析不同微卫星状态下GC的差异和相关性。肿瘤细胞中PDL1的表达标记为PDL1[T],而肿瘤浸润免疫细胞中PD1和PDL1的表达分别标记为PD1和PDL1。采用Kaplan-Meier分析评估PD1/PDL1表达在确定总生存中的意义。使用SPSS软件进行多因素Cox回归分析。P值采用对数秩检验确定。我们的结果表明,在46例微卫星不稳定(MSI)GC中,PD1、PDL1[T]和PDL1阳性率分别为59%、35%和57%,在169例微卫星稳定(MSS)GC中分别为45%、22%和40%。与MSS GC相比,MSI GC中PD1、PDL1[T]和PDL1表达更高(分别为P = 0.109、0.090和0.044)。此外,MSI GC中CD8+T细胞和CD68+M密度高于MSS GC(分别为P = 0.537和<0.001)。此外,根据肿瘤中心和浸润前沿评估CD8+T细胞/CD68+M密度。我们发现,MSI GC浸润前沿的PD1表达与CD8+T细胞密度显著相关(P = 0.031),而MSS GC肿瘤中心和浸润前沿的PDL1表达与高CD68+M密度显著相关(分别为P = 0.001和0.014)。生存分析表明,PD1阳性和PDL1[T]/PDL1阴性GC患者的预后较好(分别为P = 0.012、0.005和0.022)。多因素Cox生存分析表明,PDL1[T]是GC的独立预后因素。结果表明,GC中不同微卫星状态下PD1/PDL1表达和免疫反应存在差异。不同微卫星状态下GC中PD1/PDL1表达与CD8+T细胞/CD68+M密度相关,尤其是在浸润前沿。表现出高PD1/PDL1表达或高CD8+T细胞/CD68+M密度的MSI GC患者可能是PD1/PDL1免疫治疗的潜在受益者。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fb7/7890312/f81c46fdb221/jcav12p1698g001.jpg

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