基于 APC 状态的 MSS/pMMR 结直肠癌免疫微环境的改变。
Alteration in the Immune Microenvironment Based on APC Status in MSS/pMMR Colon Cancer.
机构信息
Cancer Centre, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
出版信息
Dis Markers. 2022 Jul 27;2022:3592990. doi: 10.1155/2022/3592990. eCollection 2022.
INTRODUCTION
Immunotherapy is currently the most promising antitumor treatment approach. However, the colon cancer immunotherapy indication dMMR/MSI-H do not cover all colon cancer patients suitable for immunotherapy. We performed transcriptome-wide expression profile analyses of pMMR/MSS colon adenocarcinoma (COAD) specimens from TCGA database to identify a genetype signature associated with tumor immune microenvironment types (TIMTs).
METHODS
TCGA database was used to identify tumor genotypes suitable for antitumor immunotherapy. We analyzed RNA-sequencing profiles of 338 COAD targeted to the pMMR/MSS group from TCGA public dataset. The ESTIMATE and the CIBERSORT were used to analyze the pMMR/MSS COAD immune microenvironment between APC wild and APC mutation. Furthermore, we further verified the relationship between APC genotype and TIMTs and the efficacy of immunotherapy in 42 colon cancer specimens.
RESULTS
We identified that in APC-wt/MSS colon cancer, the expressions of PD-1, PD-L1, CTLA4, and CYT (GZMA and PRF1) were increased. The TMB, Immunoscore, and the proportion of CT8+ T cell infiltration also were identified increasing in these patients. And pathway enrichment analysis for differentially expressed genes (DEGs) between APC-wt and APC-mt MSS COAD was done to further explore their biological function. Similarly, the significant pathways for DEGs were mainly enriched in the immune response, extracellular matrix, and cell adhesion which involved in immune response. Specimens from 42 colon cancer patients, including 22 APC-mt/MSS and 20 APC-wt/MSS, were immunohistochemically evaluated for expression of CD8 and PD-L1. And APC-wt/MSS tumors showed significantly higher expression of CD8 and PD-L1 than APC-mt/MSS tumor. Moreover, APC-wt was compared with APC-mt MSS/pMMR colon cancer (DOR, 45% and 26.7%, respectively; < 0.05).
CONCLUSION
Based on the results, we found that more colon cancers of APC-wt/MSS are classified by TMIT I. And APC-wt/MSS colon cancer patients are more likely to benefit from antitumor immunotherapy.
简介
免疫疗法是目前最有前途的抗肿瘤治疗方法。然而，结直肠癌免疫治疗的指征 dMMR/MSI-H 并不涵盖所有适合免疫治疗的结直肠癌患者。我们对 TCGA 数据库中 pMMR/MSS 结肠腺癌 (COAD) 标本进行了全转录组表达谱分析，以确定与肿瘤免疫微环境类型 (TIMTs) 相关的基因型特征。
方法
使用 TCGA 数据库鉴定适合抗肿瘤免疫治疗的肿瘤基因型。我们分析了来自 TCGA 公共数据集的 338 例靶向 pMMR/MSS 组的 COAD 的 RNA 测序图谱。ESTIMATE 和 CIBERSORT 用于分析 APC 野生型和 APC 突变型 pMMR/MSS COAD 之间的免疫微环境。此外，我们进一步验证了 APC 基因型与 TIMTs 以及免疫治疗在 42 例结肠癌标本中的疗效之间的关系。
结果
我们发现，在 APC-wt/MSS 结肠癌中，PD-1、PD-L1、CTLA4 和 CYT（GZMA 和 PRF1）的表达增加。这些患者的 TMB、免疫评分和 CT8+T 细胞浸润比例也增加。并且对 APC-wt 和 APC-mt MSS COAD 之间差异表达基因 (DEGs) 进行了通路富集分析，以进一步探讨其生物学功能。同样，DEGs 的显著通路主要富集在免疫反应、细胞外基质和细胞黏附中，这些通路都与免疫反应有关。对 42 例结肠癌患者的标本进行了 CD8 和 PD-L1 的免疫组织化学评估，包括 22 例 APC-mt/MSS 和 20 例 APC-wt/MSS。APC-wt/MSS 肿瘤的 CD8 和 PD-L1 表达明显高于 APC-mt/MSS 肿瘤。此外，与 APC-mt MSS/pMMR 结肠腺癌相比，APC-wt 与 APC-mt MSS/pMMR 结肠腺癌的差异有统计学意义（OR，分别为 45%和 26.7%；<0.05）。
结论
基于这些结果，我们发现更多的 APC-wt/MSS 结直肠癌被归类为 TIMT I。APC-wt/MSS 结直肠癌患者更有可能从抗肿瘤免疫治疗中获益。
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