PO.IM02.03 · 免疫学

内含子保留标志着一种髓系偏斜的免疫荒漠，并提名H. pylori阳性胃癌中ICI无应答的标志物

Intron retention marks a myeloid‑skewed immune desert and nominates an ICI nonresponse marker in H. pylori -positive gastric cancer

编号 2885 展板 25 时间 4/20 02:00–05:00 区域 Section 9 主讲 Daisuke Takayanagi, MD;PhD

分会场 Microbiome, Inflammation, and Response to Immunotherapy in Cancer

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作者与单位 Authors & Affiliations

Daisuke Takayanagi¹, Junya Kitadani², Masahiro Katsuda², Toshiyasu ojima², Keiji Hayata², Manabu Kawai², Sinichi Hashimoto³, Kazuhiko Tagawa⁴, Toru Sugino⁴, Satoshi Wada⁵, Hiroki Yamaue⁶, Takuya Tsunoda⁷

¹Division of Medical Oncology, Showa Medical University, Tokyo, Japan,²Second Department of Surgery, Wakayama Medical University, Wakayama, Japan,³Wakayama Medical University, Wakayama, Japan,⁴Zenick.lab Corporation, Tokyo, Japan,⁵Showa Medical University, Tokyo, Japan,⁶Pancreatic Cancer Center, Division of Gastroenterological & General Surgery, Department of Surgery, Showa Medical University, Tokyo, Japan,⁷President & CEO, Showa University, Tokyo, Japan

摘要 Abstract

中文摘要

背景：免疫检查点抑制剂（ICI）在胃癌（GC）中的获益因幽门螺杆菌（Hp）状态而异。在分析转录组时，内含子保留（IR）成为Hp阳性疾病中的一个主要区分特征，但其免疫学意义仍不清楚。方法：我们分析了来自24例患者的66份RNA-seq肿瘤样本（39份Hp阳性和27份Hp阴性）。使用PSIsigma、rMATS对可变剪接（AS）进行定量。预测AS衍生的新抗原（SNAF；严格过滤），并计算质量加权的新抗原负荷。使用纯度校正的APM评分总结抗原呈递机制（APM）。使用ESTIMATE、Hallmark GSEA、ssGSEA、CIBERSORTx以及四类亚型（荒漠/免疫富集[IE]/IE纤维化/纤维化）分析肿瘤微环境（TME）特征。高IR定义为三个或更多IR事件。使用Mann-Whitney检验和Spearman相关进行统计分析，并采用BH-FDR校正。结果：在Hp感染状态间，Hp阳性肿瘤在严格过滤下具有更多的IR/AS事件和更高的总新抗原负荷；然而，IR特异性和质量加权负荷并未显著更高。在Hp阴性肿瘤中，较高质量的新抗原负荷与内在APM能力相关（ρ≈0.41，p=0.034），表明抗原-APM偶联得以保留。在Hp阳性肿瘤中，IR高（n=12）与IR低（n=27）肿瘤相比，显示更高的新抗原指标（IR衍生4 vs 1，p=4.6×10⁻⁷；加权24.1 vs 12.2，p=3.9×10⁻⁴）、G2M/E2F/MYC/有丝分裂纺锤体程序的富集（FDR<0.05）、更高的肿瘤纯度（p=0.022）、更低的ImmuneScore（p=0.0156）和StromalScore（p=0.017），以及一致归类为荒漠亚型（12/12）。NMD和剪接特征显著升高（p=0.014/0.034），CD8/IFN特征降低（p=0.034），APM评分偏向IR低肿瘤（p=0.050）。还明显存在髓系/肥大细胞偏斜模式（MDSC特征，p = 0.037；活化肥大细胞，p=0.0077；静息肥大细胞，p=0.0027）。在Hp阳性肿瘤总体中，质量加权新抗原负荷与NMD/剪接呈正相关（ρ≈0.63，p=1.9×10⁻⁵；ρ≈0.67，p=3.7×10⁻⁶），而IR负荷与CD8/IFN活性呈负相关（ρ≈−0.44，p=0.0056）。IR事件在核心APM基因中未富集。结论：在Hp阳性GC中，高IR定义了一种增殖性、NMD/剪接应激、髓系/肥大细胞偏斜的免疫荒漠微环境，其特征是新抗原-APM去偶联。该表型与有限的ICI获益一致，将高IR确定为ICI无应答的潜在预测标志物，支持前瞻性验证以及对重编程髓系富集TME或调节剪接/NMD通路的ICI为基础方案进行假设驱动的评估。

查看英文原文 English abstract

Background: The benefits of immune checkpoint inhibitors (ICIs) in gastric cancer (GC) vary according to the Helicobacter pylori (Hp) status. While profiling transcriptomes, intron retention (IR) emerged as a major distinguishing feature in Hp-positive disease, but its immunologic significance remains unclear. Methods: We analyzed 66 RNA-seq tumor samples (39 Hp-positive and 27 Hp-negative) from 24 patients. Alternative splicing (AS) were quantified USING PSIsigma, rMATS. AS-derived neoantigens were predicted (SNAF; strict filters), and a quality-weighted neoantigen burden was calculated. Antigen-presentation machinery (APM) was summarized using a purity-adjusted APM score. Tumor microenvironment (TME) features were profiled using ESTIMATE, Hallmark GSEA, ssGSEA, CIBERSORTx, and a four-class subtype (desert/immune-enriched [IE]/IE fibrotic/fibrotic). High IR was defined as three or more IR events. Statistical analysis was performed using the Mann-Whitney test and Spearman correlation, with BH-FDR correction. Results: Across Hp infection status, Hp-positive tumors harbored more IR/AS events and a higher total neoantigen burden under strict filters; however, IR-specific and quality-weighted burdens were not significantly higher. In Hpnegative tumors, higherquality neoantigen burden correlated with intrinsic APM capacity (ρ≈0.41, p=0.034), indicating preserved antigen-APM coupling. Within Hp-positive tumors, IRhigh (n=12) versus IRlow (n=27) tumors showed higher neoantigen metrics (IRderived 4 vs 1, p=4.6×10⁻⁷; weighted 24.1 vs 12.2, p=3.9×10⁻⁴), enrichment of G2M/E2F/MYC/mitotic spindle programs (FDR<0.05), higher tumor purity (p=0.022), lower ImmuneScore (p=0.0156) and StromalScore (p=0.017), and uniform classification as the Desert subtype (12/12). NMD and splicing signatures were significantly elevated (p=0.014/0.034), CD8/IFN signatures were reduced (p=0.034), and the APM score favored IRlow tumors ( p=0.050). A Myeloid/mastcell-skewed pattern was also evident (MDSC signature, p = 0.037; activated mast cells, p=0.0077; resting mast cells, p=0.0027). In Hp-positive tumors overall, quality-weighted neoantigen burden correlated positively with NMD/splicing (ρ≈0.63, p=1.9×10⁻⁵; ρ≈0.67, p=3.7×10⁻⁶), while IR burden correlated negatively with CD8/IFN activity (ρ≈−0.44, p=0.0056). IR events were not enriched in core APM genes. Conclusions: In Hp-positive GC, high IR defines a proliferative, NMD/splicing-stressed, myeloid/mastcell-skewed immunedesert microenvironment characterized by neoantigen-APM uncoupling. This phenotype aligns with limited ICI benefit, identifying high IR as a potential predictive marker of ICI nonresponse, supporting prospective validation and hypothesis-driven evaluation of ICI-based regimens that reprogram myeloid-rich TMEs or modulate splicing/NMD pathways.

利益披露 Disclosure

D. Takayanagi, Zenick.lab Corporation Independent Contractor. J. Kitadani, None.. T. ojima, None.. K. Hayata, None.. M. Kawai, None. K. Tagawa, Zenick.lab Corporation Employment. T. Sugino, Zenick.lab Corporation g., Board of Directors, non-salaried role). H. Yamaue, None.

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