LBPO.CL02 · 临床研究 · Late-Breaking

空间组织的肿瘤、基质和免疫细胞生态位的动态相互作用可预测复发或转移性头颈部鳞状细胞癌（RM-HNSCC）对免疫检查点阻断（ICB）的疗效

Dynamic interactions of spatially organized tumor, stromal and immune cellular niches predict outcome to immune checkpoint blockade (ICB) in recurrent or metastatic head and neck squamous cell carcinoma (RM-HNSCC)

编号 LB122 展板 9 时间 4/20 09:00–12:00 区域 Section 52 主讲 Grégoire Marret, MD;PhD

分会场 Late-Breaking Research: Clinical Research 2

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作者与单位 Authors & Affiliations

Grégoire Marret¹, Jinsu An², Farnoosh Abbas Aghababazadeh³, Kewei Ni³, Lucas Penny³, Martin Hyrcza⁴, Ben X. Wang³, Enrique Sanz-Garcia¹, Anna Spreafico¹, Giselle Boukhaled³, Simone Stone³, Aaron R. Hansen¹, Troy Ketela³, Benjamin Haibe-Kains³, Scott V. Bratman³, Pinaki Bose⁵, Lillian L. Siu¹

¹Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada,²Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada,³Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada,⁴Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada,⁵Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

摘要 Abstract

中文摘要

背景：空间转录组学已揭示原发性口腔鳞状细胞癌中保守的肿瘤核心（TC）和前沿边缘（LE）结构（Arora和Bose等，Nat Commun 2023）。恶性状态的空间组织及肿瘤微环境（TME）相互作用是否可预测RM-HNSCC的免疫治疗反应尚不明确。方法：在两项研究者发起的研究INSPIRE（NCT02644369）和IOKIN（NCT04606940）中，采集了来自20例未接受过ICB治疗、接受pembrolizumab/nivolumab治疗的RM-HNSCC患者的28份肿瘤活检样本（19份治疗前、7份治疗中、2份治疗后），使用10x Visium进行分析。恶性区域通过基于参考的解卷积、病理审查以及TC/LE基因特征来界定。恶性亚簇使用Ingenuity Pathway Analysis进行功能注释。拷贝数变异（CNV）分析使用inferCNV。对癌症相关成纤维细胞（CAFs）和肿瘤相关巨噬细胞（TAMs）亚群进行了表征。细胞间相互作用使用CellChat进行推断。结果：我们分析了9,819个恶性点位和16,269个非恶性点位。除保守的TC和LE状态外，还识别出不同的增殖（上调细胞周期检查点和DNA合成通路）和中性粒细胞浸润（上调中性粒细胞脱颗粒和NETosis通路）的恶性区室。尽管存在空间分隔和转录差异，所有恶性生态位共享一个共同的CNV骨架（3q、8q、11q13扩增；3p缺失），提示TME驱动的表型可塑性是肿瘤内异质性的基础。增殖性恶性区室充当主要的信号枢纽，具有最强的CAF互作（IFN-I、WNT），并作为免疫检查点配体（PD-L1/TGFbeta/PVR）的主要来源。应答者在ICB治疗后表现出myCAF耗竭，将CAF重塑确定为关键的应答守门因素。无监督聚类揭示了免疫允许型（TAMs邻近增殖和中性粒细胞浸润区域）与免疫受限型（CAFs邻近LE）状态，二者PFS存在差异（HR=0.31；95% CI 0.09-1.01；p=0.05）。空间TME特征应用于bulk转录组学时仍保持预测价值，产生了一个免疫炎症特征，该特征在7种癌症类型的1,936例接受ICB治疗的患者（26个队列）中得到验证，可预测更优的PFS（HR=0.79；95% CI 0.63-0.98；p=0.03）和应答（OR=0.32；95% CI 0.12-0.87；p=0.03）。结论：在RM-HNSCC及多种癌症类型中，空间组织的恶性可塑性以及肿瘤-基质-免疫相互作用（而非仅肿瘤基因组学）决定了免疫治疗敏感性，确立了空间TME结构作为ICB反应的临床相关决定因素。

查看英文原文 English abstract

Background: Spatial transcriptomics has revealed conserved tumor core (TC) and leading edge (LE) architectures in primary oral squamous cell carcinoma (Arora and Bose et al . Nat Commun 2023). Whether spatial organization of malignant states and tumor microenvironment (TME) interactions predict immunotherapy response in RM-HNSCC is unknown. Methods: 28 tumor biopsies (19 pre-treatment, 7 on-treatment, 2 post-treatment) from 20 ICB-naive RM-HNSCC patients treated with pembrolizumab/nivolumab in 2 investigator-initiated studies, INSPIRE (NCT02644369) and IOKIN (NCT04606940), were profiled using 10x Visium. Malignant regions were defined by reference-based deconvolution, pathological review, and TC/LE gene signatures. Malignant subclusters were functionally annotated using Ingenuity Pathway Analysis. Copy number variation (CNV) analysis used inferCNV. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) subsets were characterized. Cell-cell interactions were inferred using CellChat. Results: We analyzed 9,819 malignant and 16,269 non-malignant spots. Beyond conserved TC and LE states, distinct cycling (upregulating cell cycle checkpoints and DNA synthesis pathways) and neutrophil-inflamed (upregulating neutrophil degranulation and NETosis pathways) malignant compartments were identified. Despite spatial segregation and transcriptional divergence, all malignant niches shared a common CNV backbone (3q, 8q, 11q13 gains; 3p loss), suggesting TME-driven phenotypic plasticity underlies intratumoral heterogeneity. Cycling malignant compartments functioned as dominant signaling hubs, with strongest CAF engagement (IFN-I, WNT) and acting as major sources of immune checkpoint ligands (PD-L1/TGFbeta/PVR). Responders showed myCAF depletion post-ICB, identifying CAF remodeling as a key response gatekeeper. Unsupervised clustering revealed immune-permissive (TAMs adjacent to cycling and neutrophil-inflamed regions) versus immune-constrained (CAFs near LE) states, with differential PFS (HR=0.31; 95% CI 0.09-1.01; p=0.05). Spatial TME features retained predictive value when applied to bulk transcriptomics, yielding an immune-inflamed signature validated in 1,936 ICB-treated patients (26 cohorts) across 7 cancer types, predicting improved PFS (HR=0.79; 95% CI 0.63-0.98; p=0.03) and response (OR=0.32; 95% CI 0.12-0.87; p=0.03). Conclusions: Spatially organized malignant plasticity and tumor-stroma-immune interactions, rather than tumor genetics alone, govern immunotherapy sensitivity in RM-HNSCC and across cancer types, establishing spatial TME architecture as a clinically relevant determinant of ICB response.

利益披露 Disclosure

G. Marret, Novartis ). J. An, None.. F. Abbas Aghababazadeh, None.. K. Ni, None.. L. Penny, None.. M. Hyrcza, None.. B. X. Wang, None. E. Sanz-Garcia, GSK ). Rgenta Therapeutics ). GSK Independent Contractor. A. Spreafico, None.. G. Boukhaled, None.. S. Stone, None.. A. R. Hansen, None.. T. Ketela, None.. B. Haibe-Kains, None.. S. V. Bratman, None.. P. Bose, None. L. L. Siu, Merck; Pfizer; AstraZeneca; Roche; GSK; Bayer; Voronoi; Arvinas; Marengo; Daiichi Sankyo; Bristol Myers Squibb; Amgen; LTZ Therapeutics; Tubulis; Marengo; Incyte; EMD Serono; Pangea; Systimmune; Other, Consultant/Advisory role (self). Accent; MBrace; Break Through Cancer; Other, Consultant/Advisory role (self). Merck; Novartis; Bristol-Myers Squibb; Pfizer; Boerhinger-Ingelheim; GSK; Roche/Genentech; AstraZeneca; Bayer; Abbvie; Amgen; EMD Serono; Daiichi Sankyo; Gilead; Marengo; Incyte; Lilly; LegoChem; ). Takara; Medicenna; Tubulis; ). Treadwell Therapeutics Other, Leadership role (spouse).

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