新抗原mRNA疫苗诱导支持抗pd -1治疗胃癌腹膜转移的祖细胞耗尽T细胞。

IF 5.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Gastric Cancer Pub Date : 2025-09-01 Epub Date: 2025-07-31 DOI:10.1007/s10120-025-01640-8

Koji Nagaoka, Hideyuki Nakanishi, Hiroki Tanaka, Jessica Anindita, Takeshi Kawamura, Toshiya Tanaka, Takefumi Yamashita, Akihiro Kuroda, Sachiyo Nomura, Hidetaka Akita, Keiji Itaka, Tatsuhiko Kodama, Kazuhiro Kakimi

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引用次数: 0

摘要

背景：胃癌伴腹膜转移预后较差。目前的治疗方法，包括纳武单抗联合化疗治疗晚期复发性胃癌的一线治疗，对腹膜传播的疗效有限。在这项研究中，我们评估了新抗原(neoAg)-mRNA脂质纳米颗粒（LNP）作为一种潜在的药物与抗pd -1治疗联合使用，重点研究了其对小鼠胃癌模型中neoAg特异性CD8+ T细胞反应的影响和抗肿瘤效果。方法：通过体外转录合成从小鼠胃癌YTN16细胞系中鉴定的3个neoAgs的串联小基因mRNA，并将其包封在LNPs中。流式细胞术检测脾脏和肿瘤中neoag特异性CD8+ T细胞的变化。在YTN16皮下和腹膜转移模型中，评估neoAg-mRNA-LNP疫苗单独或联合抗pd -1抗体的抗肿瘤效果。结果：neoAg-mRNA-LNP疫苗诱导的neoag特异性CD8+ T细胞的频率明显高于neoag -树突状细胞疫苗，证实其免疫原性增强。NeoAg-mRNA-LNP疫苗接种导致肿瘤明显消退，在所有治疗小鼠中实现完全根除，特别是与抗pd -1治疗联合使用时。这种效应与新ag特异性祖细胞耗竭和中间耗竭CD8+ T细胞的增加有关。在腹膜转移模型中，预防性给予neoAg-mRNA-LNP单药治疗可防止腹膜播散，并且在治疗环境中与抗pd -1联合治疗可有效抑制肿瘤生长。结论：NeoAg-mRNA-LNP疫苗可引起neoag特异性CD8+ T细胞的有效应答，并在抗pd -1治疗下增强胃癌腹膜转移的抗肿瘤效果。

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Neoantigen mRNA vaccines induce progenitor-exhausted T cells that support anti-PD-1 therapy in gastric cancer with peritoneal metastasis.

Background: Gastric cancer with peritoneal metastasis is associated with a poor prognosis. Current treatments, including the first-line therapy of combination chemotherapy with nivolumab for advanced recurrent gastric cancer, have shown limited efficacy against peritoneal dissemination. In this study, we evaluated neoantigen (neoAg)-mRNA lipid nanoparticle (LNP) as a potential agent in combination with anti-PD-1 therapy, focusing on its effects on neoAg-specific CD8⁺ T cell responses and antitumor efficacy in a murine gastric cancer model.

Methods: The mRNA, comprising a tandem minigene encoding three neoAgs identified from the murine gastric cancer YTN16 cell line, was synthesized by in vitro transcription and encapsulated within LNPs. NeoAg-specific CD8⁺ T cells in the spleens and tumors were assessed by flow cytometry. The antitumor efficacy of the neoAg-mRNA-LNP vaccine, alone or in combination with anti-PD-1 antibody, was evaluated in both subcutaneous and peritoneal metastasis models of YTN16.

Results: The neoAg-mRNA-LNP vaccine induced significantly higher frequencies of neoAg-specific CD8⁺ T cells than the neoAg-dendritic cell vaccine, confirming its enhanced immunogenicity. NeoAg-mRNA-LNP vaccination led to robust tumor regression, achieving complete eradication in all treated mice, especially when combined with anti-PD-1 therapy. This effect was associated with an increase in neoAg-specific progenitor-exhausted and intermediate-exhausted CD8⁺ T cells. In a peritoneal metastasis model, neoAg-mRNA-LNP monotherapy prevented peritoneal dissemination when administered prophylactically, and combination therapy with anti-PD-1 effectively suppressed tumor growth in a therapeutic setting.

Conclusions: NeoAg-mRNA-LNP vaccines elicit potent neoAg-specific CD8⁺ T cell responses and show enhanced antitumor efficacy with anti-PD-1 therapy in gastric cancer with peritoneal metastasis.

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来源期刊

Gastric Cancer 医学-胃肠肝病学

CiteScore

14.70

自引率

2.70%

发文量

审稿时长

6-12 weeks

期刊介绍： Gastric Cancer is an esteemed global forum that focuses on various aspects of gastric cancer research, treatment, and biology worldwide. The journal promotes a diverse range of content, including original articles, case reports, short communications, and technical notes. It also welcomes Letters to the Editor discussing published articles or sharing viewpoints on gastric cancer topics. Review articles are predominantly sought after by the Editor, ensuring comprehensive coverage of the field. With a dedicated and knowledgeable editorial team, the journal is committed to providing exceptional support and ensuring high levels of author satisfaction. In fact, over 90% of published authors have expressed their intent to publish again in our esteemed journal.