Nakajima Kosei, Ino Yoshinori
Division of Molecular Pathology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, 104-0045, Tokyo Japan.
Division of Translational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, 104-0045, Tokyo Japan.
Oncol Res. 2025 Jun 26;33(7):1769-1779. doi: 10.32604/or.2025.063419. eCollection 2025.
Neoadjuvant/preoperative therapy (NAT) involves the administration of chemotherapy, with or without radiation, prior to surgical resection. This approach is commonly used for locally advanced tumors to reduce tumor volume, improve resectability, and minimize the need for extensive surgical procedures. While NAT has been shown to be effective in inducing local anti-tumor immunity in potentially resectable solid tumors, the underlying molecular mechanisms remain poorly understood.
Cohort samples from pancreatic cancer patients who underwent NAT (n = 26) and those who did not (n = 20) were analyzed. Changes in the immune microenvironment induced by NAT were assessed using stratified bioinformatic approaches, including heatmap analysis of immune-related genes selected via Gene Ontology, Gene Set Enrichment Analysis (GSEA) with the immunologic signature database, and Ingenuity Pathway Analysis (IPA). Findings were further validated through immunohistochemical analysis.
A comprehensive, stratified evaluation integrating pathological and bioinformatic approaches revealed that NAT induced the upregulation of 212 genes, including DC-SIGN (CD209), and activated 13 immune-associated pathways, such as T-cell receptor (TCR) signaling. Additionally, NAT promoted an increased shift toward CD8 (+) T-cell populations through the upregulation of MAL (T-cell differentiation protein). Immunohistochemical analysis further confirmed a significant accumulation of DC-SIGN (+) dendritic cells and MAL (+) lymphocytes in NAT-treated patients.
NAT enhances anti-tumor immunity by promoting CD8 (+) T-cell generation through the activation of DC-SIGN (+) dendritic cells and MAL (+) lymphocytes. This study is the first to report an increase in MAL (+) lymphocytes following NAT. Given its potential significance, further investigation in other solid tumors treated with NAT is warranted.
新辅助/术前治疗（NAT）包括在手术切除前给予化疗，可联合或不联合放疗。这种方法常用于局部晚期肿瘤，以减小肿瘤体积、提高可切除性并尽量减少广泛手术操作的必要性。虽然NAT已被证明在潜在可切除实体瘤中诱导局部抗肿瘤免疫有效，但其潜在分子机制仍知之甚少。
分析了接受NAT的胰腺癌患者（n = 26）和未接受NAT的胰腺癌患者（n = 20）的队列样本。使用分层生物信息学方法评估NAT诱导的免疫微环境变化，包括通过基因本体选择的免疫相关基因的热图分析、使用免疫特征数据库的基因集富集分析（GSEA）以及 Ingenuity 通路分析（IPA）。通过免疫组织化学分析进一步验证研究结果。
综合病理和生物信息学方法的分层评估显示，NAT诱导了212个基因的上调，包括DC-SIGN（CD209），并激活了13条免疫相关通路，如T细胞受体（TCR）信号通路。此外，NAT通过上调MAL（T细胞分化蛋白）促进了向CD8(+) T细胞群体的增加转变。免疫组织化学分析进一步证实，在接受NAT治疗的患者中，DC-SIGN(+)树突状细胞和MAL(+)淋巴细胞显著聚集。
NAT通过激活DC-SIGN(+)树突状细胞和MAL(+)淋巴细胞促进CD8(+) T细胞生成，从而增强抗肿瘤免疫。本研究首次报道了NAT后MAL(+)淋巴细胞增加。鉴于其潜在意义，有必要对接受NAT治疗的其他实体瘤进行进一步研究。
