PO.TB10.06 · 肿瘤生物学

头颈部鳞状细胞癌（SCCHN）的空间结构：一项IMMUcan/EORTC分析

Spatial architecture of head and neck squamous cell carcinoma (SCCHN): An IMMUcan/EORTC analysis

编号 812 展板 24 时间 4/19 02:00–05:00 区域 Section 32 主讲 Lucas Michon

分会场 Spatial Protein Profiling and Multi-Modal Mapping of Tumor and Circulating Ecosystems

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作者与单位 Authors & Affiliations

Lucas Michon¹, Athénaïs van der Elst², Daniel Herrero-Saboya³, Marie Morfouace⁴, Preethi Devanand⁵, Robin Liechti⁶, Daniel Schulz⁷, Maya Persoons¹, Sylvie Rusakiewicz⁵, Nils Eling⁸, Paul-Antoine Nicolas³, Stephanie Renaud-Tissot⁵, Bernd Bodenmiller⁹, Henoch Hong¹⁰, Rachel Galot¹¹, Paolo bossi¹², Julio Oliveira¹³, Florian Estrade¹⁴, Caroline Even¹⁵, Sophie E. Lucas¹⁶, Loredana Martignetti³, Céline Lefebvre¹⁷, jean-pascal Machiels¹¹, Pierre Saintigny¹

¹Ctr. Léon Bérard, Lyon, France,²Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium,³Institut Curie, Paris, France,⁴Marie Morfouace (Individual), Villejuif, France,⁵Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland,⁶SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland,⁷ETH Zurich, Switzerland,⁸Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland,⁹University of Zurich, Zurich, Switzerland,¹⁰Merck KGaA, Darmstadt, Germany,¹¹Université catholique de Louvain, Brussels, Belgium,¹²Humanitas University,¹³Instituto Portugues de Oncologia de Porto Franscisco Gentil, Porto, Portugal,¹⁴Centre Eugène Marquis, Rennes, France,¹⁵Gustave Roussy, Villejuif, France,¹⁶Catholic University of Louvain, Brussels, Belgium,¹⁷Servier Research & Development, Saclay, France

摘要 Abstract

中文摘要

背景：SCCHN的空间结构与临床及分子特征之间的关联目前尚不明确。方法：采用成像质谱流式技术（imaging mass cytometry）对253例复发/转移性（R/M）SCCHN样本（包括77例免疫治疗（IO）前样本）进行分析，以研究癌细胞及13种免疫细胞类型（PMID 40930089）。分析了全局细胞密度（cellD，n/mm²）和细胞邻域（CN）。计算了局部cellD（癌细胞内免疫浸润/排斥程度）以及两两表型之间的细胞相互作用系数，二者均独立于全局cellD。采用加权相关网络分析检测细胞相互作用系数的模块。探讨了TLS及癌细胞状态[缺氧、细胞周期活跃、EMT、β2-微球蛋白（beta2m）缺失]。将数据与IO原发性耐药与继发性耐药（R）、HPV状态、生存、DNA和RNA图谱进行相关性分析。结果：共鉴定出8个CN（纯癌细胞、内部及外部（癌/间质）界面、浆细胞聚集、中性粒细胞（PMN）、巨噬细胞/壁细胞、T细胞以及巨噬细胞/壁细胞/T细胞）。HPV+肿瘤的外部界面减少。难治性HNSCC的界面减少且DC浸润较低。在外部界面相较于内部界面、内部界面相较于纯癌细胞CN中，癌细胞缺氧程度逐渐增高，或beta2m表达逐渐降低，EMT逐渐减弱。总体而言，癌细胞状态具有深远影响，可增加（周期活跃的癌细胞）或减少（缺氧的癌细胞）免疫细胞浸润。我们鉴定出3个SCCHN聚类：C1（45%）具有较高的全局免疫cellD但较低的局部cellD；C2（40%）为免疫荒漠型；C3（15%）为高度浸润型（局部cellD高），且在接受IO治疗的患者中生存最佳。基于RNA的“经典型”SCCHN几乎全部为C2。C3富集于细胞外基质组织、免疫细胞及迁移相关通路。特定的TLS CN包括B细胞区、生发中心和浆细胞聚集。HPV+肿瘤的B细胞区增加，但浆细胞聚集减少。全部3种TLS CN在难治性SCCHN中以及原发性耐药相较于继发性耐药中均减少。在接受IO治疗的患者中，TLS的存在改善了预后，且TLS距癌细胞越近，预后越好。虽然PMN与免疫细胞之间的相互作用与较差预后相关，但PMN浸润癌细胞与生存改善相关，T细胞与癌细胞或与HLADR、MacCD163及壁细胞相互作用亦是如此。最后，突变通常与免疫细胞相对于癌细胞的更多排斥相关，例如在RB1突变以及FAT4-PTPRT突变的SCCHN中，T-CD8和PMN分别更多被排斥；BAP1和HRAS突变分别导致MacCD163-NK-壁细胞-HLADR-浆细胞及B细胞被排斥。结论：我们提供了对SCCHN空间结构的全面描述及其临床/分子相关性分析。

查看英文原文 English abstract

Background : The association of spatial architecture of SCCHN with clinical and molecular characteristics is poorly understood. Methods : 253 recurrent/metastatic (R/M) SCCHN, including 77 pre-immunotherapy (IO) samples, were analyzed by imaging mass cytometry to study cancer cells and 13 immune cell types (PMID 40930089) . Global cell densities (cellD, n/mm 2 ) and cellular neighborhoods (CN) were analyzed. Local cellD (degree of immune infiltration/exclusion within cancer cells) and cell interaction coefficients between pair-wise phenotypes, both independent of global cellD, were computed. Weighted correlation network analysis was used to detect modules of cell interaction coefficients. TLS and cancer cells states [hypoxic, cell cycling, EMT, beta2-microglobulin (beta2m) loss] were explored. Data were correlated with IO primary vs. secondary resistance (R), HPV status, survival, DNA and RNA profiles. Results : 8 CN were identified (pure cancer cells, internal and external (cancer/stroma) interfaces, aggregation of plasma cells, neutrophils (PMN), macrophages/mural cells, T-cells and macrophages/mural/T-cells). HPV+ tumors had decreased external interface. Refractory HNSCC had decreased interfaces and lower DC infiltration. Cancer cells were increasingly hypoxic or had decreasing beta2m expression and decreasing EMT in external interface vs. internal interface vs. pure cancer cells CNs. Overall, cancer cell states had profound impact by either increasing (cycling cancer cells) or decreasing (hypoxic cancer cells) immune cells infiltration. We identified 3 clusters of SCCHN: C1 (45%) had high global immune cellD but low local cellD; C2 (40%) was desertic; C3 (15%) was highly infiltrated (high local cellD) and had the best survival in IO-treated pts. RNA-based ‘Classical' SCCHN were almost exclusively C2. C3 was enriched in extracellular matrix organization, immune cell and migration. Specific TLS CN included B compartment, germinal center and plasma aggregation. HPV+ tumors had increased B compartment but decreased plasma aggregation. All 3 TLS CN were decreased in refractory SCCHN and in primary vs. secondary R. In IO-treated pts, TLS presence improved outcome and the closer TLS were to cancer cells, the better was the outcome. While the interaction between PMN and immune cells was associated with worse outcome, PMN infiltrating cancer cells was associated with improved survival together with T-cells interacting with cancer cells or with HLADR, MacCD163 and mural cells. Finally, mutations were generally associated with more exclusion of immune to cancer cells e.g. T-CD8 and PMN were more excluded in SCCHN mutated for RB1 and FAT4-PTPRT respectively; and BAP1 and HRAS mutations had exclusion of MacCD163-NK-mural-HLADR-plasma and B cells respectively. Conclusion: we provide a comprehensive description and clinical/molecular correlatives of the spatial architecture of SCCHN.

利益披露 Disclosure

L. Michon, None.. A. van der Elst, None.. D. Herrero-Saboya, None.. P. Devanand, None.. R. Liechti, None.. M. Persoons, None.. S. Rusakiewicz, None.. N. Eling, None.. P. Nicolas, None.. S. Renaud-Tissot, None.. B. Bodenmiller, None. H. Hong, Merck Employment. R. Galot, None.. J. Oliveira, None.. F. Estrade, None.. C. Even, None.. L. Martignetti, None.. C. Lefebvre, None. J. Machiels, Pfizer Other, Advisory board member or speaker with honoraria. Roche Other, Advisory board member or speaker with honoraria. Bayer Other, Advisory board member or speaker with honoraria. Merck Serono Other, Advisory board member or speaker with honoraria. GSK Advisory board member or speaker with honoraria. Boerhinger Other, Advisory board member or speaker with honoraria. BMS Other, Advisory board member or speaker with honoraria. Novartis Advisory board member or speaker with honoraria. Incyte Other, Advisory board member or speaker with honoraria. Cue Biopharma Other, Advisory board member or speaker with honoraria. ALX Other, Advisory board member or speaker with honoraria. iTEOS Advisory board member or speaker with honoraria. eTheRNA Other, Advisory board member or speaker with honoraria. NEKTAR Other, Advisory board member or speaker with honoraria. F-Star Other, Advisory board member or speaker with honoraria. Seagen Other, Advisory board member or speaker with honoraria. Genmab Other, Advisory board member or speaker with honoraria. Astellas Other, Advisory board member or speaker with honoraria. CureVac Other, Advisory board member or speaker with honoraria. MSD Other, Advisory board member or speaker with honoraria. P. Saintigny, HTG Molecular Diagnostics Other, Honoraria. Inivata Other, Honoraria. ArcherDx Other, Honoraria. Bristol Myer Squibb Travel, Other, Honoraria. Roche Molecular Diagnostics Travel, Other, Honoraria. OSE Immunotherapeutics ), Travel. Roche ), Travel. Astra-Zeneca ), Travel. Novartis ). BMS Foundation ). Illumina ), Travel. Omicure ).

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