PO.TB10.08 · 肿瘤生物学
空间组织的转录程序和肿瘤-基质界面塑造微卫星高度不稳定性胃肠道肿瘤的免疫治疗反应
Spatially organized transcriptional programs and tumor-stroma interfaces shape immunotherapy response in microsatellite instability-high gastrointestinal cancers
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摘要 Abstract
中文摘要
背景：免疫检查点阻断（ICB）显著改善了微卫星高度不稳定性（MSI-H）胃肠道肿瘤的预后，然而超过半数患者尽管初始肿瘤消退，却未能达到持久缓解。仅依据MSI状态和影像学反应指导的临床决策，在预测长期获益或为手术和治疗调整提供信息方面能力有限。因此，开发具有空间信息的持续反应分子预测因子将满足MSI-H肿瘤管理中的一项关键未满足需求。
方法：对来自13例胃癌、结直肠癌或食管癌患者的18份肿瘤标本进行了空间转录组分析，包括11例MSI-H和2例MSS肿瘤，标本于ICB治疗前后采集。所有组织均使用10x Genomics Visium平台进行检测。将病理学指导的位点注释与转录元程序分析、空间反卷积、生态位相互作用图谱和配体-受体建模相结合，以表征持续完全缓解者（CR）与非持续缓解者（NR）之间的肿瘤-免疫-基质组织。
结果：我们发现肿瘤细胞元程序（MP）在不同反应组之间表现出不同的空间梯度。上皮-间质转化MP在治疗前NR（pre-NR）肿瘤组织的侵袭边缘富集，并向核心减弱，而高周期-干扰素MP在治疗前CR肿瘤组织的外周达到峰值。这些发现表明转录程序在肿瘤内呈空间区室化分布。接下来，我们研究了肿瘤微环境（TME）的空间组织在反应组之间的差异。在治疗前CR肿瘤中，恶性细胞与B细胞和滤泡辅助性T细胞在三级淋巴结构（TLS）内共定位，而在治疗前NR肿瘤中，它们与巨噬细胞和癌症相关成纤维细胞相关联。值得注意的是，CR肿瘤的TLS无论其成熟状态如何均表现出更强的免疫激活特征。细胞-细胞通讯分析进一步揭示，持续CR肿瘤在肿瘤-基质界面处存在免疫激活，与NR肿瘤中的免疫抑制信号形成对比。
结论：我们的研究揭示了MSI-H胃肠道肿瘤对ICB差异反应背后的不同空间和转录程序，凸显了肿瘤-免疫-基质组织在塑造治疗结局和指导未来增强免疫治疗疗效策略中的关键作用。
查看英文原文 English abstract
Background : Immune checkpoint blockade (ICB) has significantly improved outcomes in microsatellite instability-high (MSI-H) gastrointestinal cancers, yet more than half of patients do not achieve durable remission despite initial tumor regression. Clinical decisions guided solely by MSI status and radiographic response provide limited ability to anticipate long-term benefit or inform choices regarding surgery and treatment modification. The development of spatially informed molecular predictors of sustained response would therefore address a critical unmet need in the management of MSI-H tumors.
Methods : Spatial transcriptomic profiling was performed on 18 tumor specimens from 13 patients with gastric, colorectal, or esophageal cancers, including 11 MSI-H and 2 MSS tumors, collected before and after ICB therapy. All tissues were assayed using the 10x Genomics Visium platform. Pathology-guided spot annotation was combined with transcriptional Meta-program analysis, spatial deconvolution, niche interaction mapping, and ligand-receptor modeling to characterize tumor-immune-stromal organization across sustained complete responders (CR) and non-sustained responders (NR).
Results : We found that tumor cell meta-programs (MPs) exhibited distinct spatial gradients across different response groups. The epithelial-mesenchymal transition MPs was enriched at the invasive margin of pre-treatment NR (pre-NR) tumor tissue and diminished toward the core, while the Cycling-high-Interferon MPs peaked at the periphery of pre-CR tumor tissue. These findings indicate that transcriptional programs are spatially compartmentalized within the tumor. Next, we investigated how the spatial organization of the tumor microenvironment (TME) differed between response groups. In pre-CR tumors, malignant cells colocalized with B cells and T follicular helper cells within tertiary lymphoid structures (TLSs), whereas in pre-NR tumors, they were associated with macrophages and cancer-associated fibroblasts. Notably, TLSs from CR tumors exhibited stronger immune activation signatures irrespective of their maturation state. Cell-cell communication analysis further revealed immune activation at the tumor-stroma interface in sustained-CR tumors, contrasting with immunosuppressive signaling in NR tumors.
Conclusions : Our study reveals distinct spatial and transcriptional programs underlying differential responses to ICB in MSI-H gastrointestinal cancers, highlighting the pivotal role of tumor-immune-stromal organization in shaping therapeutic outcomes and guiding future strategies to enhance immunotherapy efficacy.
利益披露 Disclosure
X. Han, None..
K. Yamashita, None..
M. Pizzi, None..
K. Cho, None..
E. Dai, None..
H. Yoshimura, None..
R. Waters, None..
Q. Gan, None..
F. Yin, None..
I. Martins, None..
J. Willis, None..
M. B. Murphy, None..
J. Li, None..
B. D. Badgwell, None..
J. A. Ajani, None.