Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan, R.O.C.
Centers of Genomic and Precision Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.
Sci Rep. 2021 Apr 27;11(1):9080. doi: 10.1038/s41598-021-88648-z.
Single immunotherapy fails to demonstrate efficacy in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Research on immune reactions before and after systemic agents for mCRC is warranted. Our study examined cell line models to compare the expression of immune surface markers on colon cancer cells before and after chemotherapy agents. We also elucidated mechanisms underlying the effects of chemotherapy agents on immune surface markers. We used real-world clinical samples with NanoString analysis and the Perkin-Elmer Opal multiplex system. We established that chemotherapy agents, particularly 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, stimulated the expression of stimulatory MHC class I alleles through stimulation the pathway of transporters associated with antigen processing 1 and 2 (TAP1 and TAP2) in cell line models. Application of infected cell protein 47 (ICP-47), a specific inhibitor of the TAP1/TAP2, significantly inhibited expression of TAP1/TAP2 and also inhibited the expression of the downstream MHC class I. In the functional assay, SN-38 significantly promoted the phagocytosis of colon cancer cells by monocyte-derived dendritic cells (MoDCs). We confirmed that the expression of major histocompatibility complex (MHC) class I, significantly increased after first-line chemotherapy and targeted therapy in the samples of real-world patients with de novo mCRC. Our study provides new insights for novel immunotherapy combinations.
单一免疫疗法未能在微卫星稳定（MSS）转移性结直肠癌（mCRC）患者中显示出疗效。有必要研究 mCRC 系统治疗前后的免疫反应。我们的研究使用细胞系模型来比较化疗药物治疗前后结肠癌细胞表面免疫标志物的表达。我们还阐明了化疗药物对免疫表面标志物的作用机制。我们使用了带有 NanoString 分析和 Perkin-Elmer Opal 多重系统的真实世界临床样本。我们发现，化疗药物，特别是伊立替康的活性代谢物 7-乙基-10-羟基喜树碱（SN-38），通过刺激转运体相关抗原加工 1 和 2（TAP1 和 TAP2）通路，刺激细胞系模型中刺激 MHC 类 I 等位基因的表达。感染细胞蛋白 47（ICP-47），TAP1/TAP2 的特异性抑制剂，应用后显著抑制 TAP1/TAP2 的表达，也抑制下游 MHC 类 I 的表达。在功能测定中，SN-38 显著促进单核细胞衍生树突状细胞（MoDC）对结肠癌细胞的吞噬作用。我们证实，在新诊断的 mCRC 患者真实世界样本中，一线化疗和靶向治疗后 MHC 类 I 的表达显著增加。我们的研究为新的免疫治疗组合提供了新的见解。
