PO.CL01.02 · 临床研究

接受免疫治疗（IO）的局部晚期/转移性头颈部鳞状细胞癌（LA/M SCCHN）患者临床结局的单细胞和空间分辨决定因素

Single cell and spatially resolved determinants of the clinical outcome of patients (pts) treated with locally advanced/metastatic head and neck squamous cell carcinoma (LA/M SCCHN) treated with immunotherapy (IO)

编号 1037 展板 5 时间 4/19 02:00–05:00 区域 Section 41 主讲 Pierre Saintigny, MD;PhD

分会场 Biomarkers Predictive of Therapeutic Benefit 2

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作者与单位 Authors & Affiliations

Mehdi Lamkhioued¹, Thimothee Casini¹, Elodie Girard², Karène Mahtouk¹, Sonia Canjura-Rodriguez¹, Valery Attignon¹, Bastien Cabarrou³, Constance Lamy², Anne Schnitzler², Frederique Penault-Llorca¹, Caroline Even⁴, Christophe Le Tourneau⁴, Ellen Van Obberghen-Schilling⁵, Nicolas Servant², Fayette Jerome¹, Nathalie Bendriss-Vermare¹, Ivan Bièche⁶, Pierre Saintigny¹

¹Ctr. Léon Bérard, Lyon, France,²Inst. Curie, Paris, France,³IUCT Oncopole, Toulouse, France,⁴Gustave Roussy, Paris, France,⁵Université côte d'Azur, Nice, France,⁶Genetics Department, Inst. Curie, Paris, France

摘要 Abstract

中文摘要

背景：我们开发了一个复合基因表达特征（cGES），包含 22 个保护性（P）基因和 19 个不利（A）基因，不依赖于肿瘤类型，将接受 IO 治疗的患者分为 3 个风险组：低危（L-）、中危（I-）和高危（H-）（摘要#6360 AACR2025）。在此，我们在一个前瞻性队列中验证其对无进展生存（PFS）和总生存（OS）的预测价值，并揭示临床结局背后的单细胞和空间决定因素。方法：（1）在来自 2 项试验（NCT03226756；NCT03412058）的 170 例 LA/M SCCHN 患者中计算 cGES。（2）接下来，我们构建了一个来自 77 例独立患者的 219,138 个细胞的 scRNAseq SCCHN 图谱（scAt），其中分别包括 19 例和 21 例归类为高危和低危的患者，并研究了两组患者之间细胞群的分布和功能状态。量化了 A 和 P 基因的细胞类型特异性富集，并推断细胞间通讯网络以识别配体-受体（L-R）相互作用。（3）使用来自 77 例 SCCHN 中 12 例（包括 3 例高危和 3 例低危患者）的去卷积 Visium 数据，绘制 cGES 的空间组织并定位特定的 L-R 相互作用。结果：（1）校正 ECOG、年龄、性别及饮酒/吸烟情况的多变量分析显示，中危和低危患者的结局显著更好。对于 PFS，风险比分别为 0.64（p=0.04）和 0.51（p=0.005）；对于 OS 分别为 0.81（p>0.05）和 0.54（p=0.015）。（2）对 scAt 的分析显示，cGES 中的 A 基因主要由上皮细胞和基质细胞表达。相反，P 基因主要由免疫细胞表达。高危肿瘤表现出改变的通讯格局，以增强的上皮连接、发育信号和普遍升高的 EGFR L-R 活性为特征，而低危肿瘤则显示出以细胞外重塑、适应性免疫激活和免疫细胞募集为主导的免疫富集网络。（3）Visium 去卷积识别出 5 个主要的细胞组成簇（C），其中上皮富集的 C2 显示最高的 A 基因表达，而 T 细胞富集的 C4/C5 显示最强的 P 基因表达。高危肿瘤表现出显著的 EGFR 配体表达，与 scAt 数据的结果一致。相反，低危肿瘤显示出增加的抗原呈递、T 细胞趋化和补体信号。结论：cGES 可靠地对预后进行分层，并反映肿瘤生态系统生物学。高危肿瘤以上皮驱动、以 EGFR 为中心的信号为主，而低危肿瘤显示出协调的炎症性 T 细胞导向程序。这些发现提示 cGES 可作为预后和机制性生物标志物，并为 EGFR-IO 联合策略改善 LA/M SCCHN 结局提供了理论依据。

查看英文原文 English abstract

Background: We developed a composite Gene Expression Signature (cGES) comprising 22 protective (P) and 19 adverse (A) genes, agnostic of the tumor type, stratifying IO-treated pts in 3 risk groups : low (L-), intermediate (I-) and high-risk (H-) (abstract#6360 AACR2025). Herein, we validate its predictive value for progression free (PFS) and overall survival (OS) in a prospective cohort and uncover the single-cell and spatial determinants underlying clinical outcomes. Methods: (1) The cGES was computed in 170 pts with LA/M SCCHN from 2 trials (NCT03226756; NCT03412058). (2) Next, we built a scRNAseq SCCHN atlas (scAt) of 219,138 cells from 77 independant pts including 19 and 21 pts classified as H-risk and L-risk respectively, and studied the distribution and functional states of cell populations between the 2 groups of pts. Cell-type-specific enrichments of A & P genes werequantified and intercellular communication networks were inferred to identify ligand-receptor (L-R) interactions. (3) Deconvoluted Visium data from 12 of the 77 SCCHN including 3 H-risk and 3 L-risk pts were used to map the spatial organization of cGES and to localize specific L-R interactions. Results: (1) Multivariate analysis adjusted for ECOG, age, gender, and alcohol/tobacco use showed that I- and L-risk pts had significantly better outcomes. For PFS, hazard ratios were 0.64 (p=0.04) and 0.51 (p=0.005), and for OS 0.81 (p>0.05) and 0.54 (p=0.015), respectively. (2) Analysis of the scAt revealed that A genes from cGES were mainly expressed by epithelial and stromal cells. Conversely, P genes were mainly expressed by immune cells. H-risk tumors exhibited an altered communication landscape marked by strengthened epithelial junctions, developmental signaling, and universally increased EGFR L-R activity, whereas L-risk tumors showed an immune-enriched network dominated by extracellular remodeling, adaptive immune activation and immune cell recruitment. (3) Visium deconvolution identified 5 major cell-composition clusters (C), with epithelial-enriched C2 showing the highest A genes expression, while T cell-enriched C4/C5 displayed the strongest P genes expression. H-risk tumors exhibited prominent EGFR ligand expression, consistent with the results from the scAt data. In contrast, L-risk tumors displayed increased antigen-presentation, T-cell chemotaxis, and complement signaling. Conclusion: cGES reliably stratified prognosis and reflects tumor ecosystem biology. H-risk tumors were dominated by epithelial-driven, EGFR-centered signaling, whereas L-risk tumors showed coordinated inflammatory T-cell-oriented programs. These findings suggest cGES as a prognostic and mechanistic biomarker, and provides a rational for EGFR-IO combination strategies to improve outcomes in LA/M SCCHN.

利益披露 Disclosure

M. Lamkhioued, None.. T. Casini, None.. E. Girard, None.. K. Mahtouk, None.. S. Canjura-Rodriguez, None.. V. Attignon, None.. B. Cabarrou, None.. C. Lamy, None.. A. Schnitzler, None.. F. Penault-Llorca, None.. C. Even, None.. C. Le Tourneau, None.. E. Van Obberghen-Schilling, None.. N. Servant, None. F. Jerome, Astrazeneca ), Other, Advisory Board. Hookipa Other, Advisory Board. Innate Pharma Advisory Board. Merck Other, Advisory Board. MSD ), Other, Advisory Board, Principal Investigator. Pfizer ), Other, Advisory Board, Principal Investigator. Roche Other, Advisory Board. Calliditas ), Principal Investigator. Isa ), Principal Investigator. Meru ), Principal Investigator. N. Bendriss-Vermare, None. P. Saintigny, HTG Molecular Diagnostics Other, Honoraria. Inivata Other, Honoraria. ArcherDx Other, Honoraria. Bristol Myer Squibb ), Travel, Other, Honoraria. Roche ), Travel, Other, Honoraria. OSE immunotherapeutics ), Travel. Astrazeneca ), Travel. Novartis ). Illumina ), Travel. Omicure ).

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