PO.IM02.01 · 免疫学

泛肿瘤分析确定了泛癌免疫原型以及CD8⁺FoxP3⁺细胞作为新型的原位生存预测因子

Tumor-agnostic analysis identified pan-cancer immune archetypes and CD8⁺FoxP3⁺ cells as novel in situ predictors of survival

编号 193 展板 13 时间 4/19 02:00–05:00 区域 Section 9 主讲 Artur Mezheyeuski

分会场 Inflammation and Cancer Progression

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作者与单位 Authors & Affiliations

Artur Mezheyeuski¹, Emma Sandberg², Max Backman³, Ali Teymur Kahraman³, Amanda Lindberg³, Carina Strell², Hans Brunnström⁴, Jutta Huvila⁵, Malin Sund⁶, Fredrik Wärnberg⁷, Bengt Glimelius³, Ina Hrynchyk⁸, Siarhei Mauchanski⁹, Salome Khelashvili¹⁰, Klara Hammarström³, Margret Agnarsdottir³, Gemma Garcia-Vicién¹¹, DAVID G. MOLLEVI¹², Aine O´Reilly¹³, Sara Corvigno¹⁴, Hanna Dahlstrand³, Johan Botling¹⁵, Ulrika Segersten⁴, Agnieszka Krzyzanowska¹⁶, Anders Bjartell⁴, Jacob Elebro⁴, Margareta Heby⁴, Sebastian Lundgren⁴, Charlotta Hedner⁴, David Borg⁴, Jenny Brändstedt⁴, Hanna Sartor⁴, Per-Uno Malmström³, Martin Johansson¹⁵, Anna Portyanko¹⁰, Björn Nodin⁴, Cecilia Lindskog³, Karin Leandersson⁴, Karin Jirström⁴, Tobias Sjöblom³, Patrick Micke³

¹Vall d’Hebron Institute of Research, Barcelona, Spain,²Uppsala University, Dept of Immunology, Genetics and Pathology, Uppsala, Sweden,³Uppsala University, Uppsala, Sweden,⁴Lund University, Lund, Sweden,⁵University of Turku, Turku, Finland,⁶Umeå University, Umeå, Sweden,⁷Sahlgrenska University Hospital Göteborg, Göteborg, Sweden,⁸City Clinical Pathologoanatomic Bureautitute (VHIR), Minsk, Belarus,⁹Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain,¹⁰N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus,¹¹IDIBELL L'Hospitalet de Llobregat Barcelona, Barcelona, Spain,¹²LABORATORI DE RECERCA TRANSLACIONAL, INSTITUT CATALA D'ONCOLOGIA, BARCELONA, Spain,¹³Karolinska Institutet, Stockholm, Sweden,¹⁴UT MD Anderson Cancer Center, Houston, TX,¹⁵Sahlgrenska Universitety Hospital Göteborg, Göteborg, Sweden,¹⁶Lund University, Malmö, Sweden

摘要 Abstract

中文摘要

免疫浸润塑造抗肿瘤反应，并与患者结局相关。然而，跨癌种比较浸润模式及其临床影响的全面研究却很匮乏。我们采用多重免疫荧光结合病理学家审校的图像分析，对来自2700余例患者的16种实体瘤类型的肿瘤免疫微环境进行了分析，以定量原位主要淋巴系和髓系亚群及其空间组织。在所有癌种中，肺癌、子宫内膜癌和高级别浆液性卵巢癌高度浸润，而前列腺癌和ER阳性乳腺癌相对呈“免疫冷”状态。与癌种无关的共识聚类解析出四种可重复的免疫原型，具有各自不同的结局，其中一个富含CD4、CD8和B细胞的免疫热组与最佳生存相关（p<0.001）。值得注意的是，肿瘤类型仅解释了免疫背景的一部分，因为大多数癌症跨越多个免疫特征组。尽管如此，基于免疫组成训练的机器学习分类器能以高准确度区分肿瘤类型（AUC=0.96），证实即便在泛癌原型之中，每种癌症仍保持可识别的免疫印记。对各个细胞类别生存关联的分析揭示，一种罕见的CD8⁺FOXP3⁺ T细胞表型成为跨癌种最强的正向预后因素（HR=0.79，95%CI:[0.70-0.89]，p=0.002）。单细胞RNA测序数据表明，CD8⁺FoxP3⁺细胞表现出两种不同的基因程序，兼具调节性和细胞毒性能力。空间定位提示CD8⁺FoxP3⁺细胞的功能具有情境依赖性，因为其邻近CD8 T细胞与较好的生存相关（10um处富集：HR=0.76，95%CI:[0.67-0.90]，p=0.0006），而邻近肿瘤细胞则与较差的预后相关（10um处富集：HR=1.29，95%CI:[1.12-1.49]，p=0.0005）。综上，我们的发现定义了既共有又具疾病特异性的泛癌免疫原型，解释了为何“免疫热”和“免疫冷”状态并不等同于单纯的浸润数量。我们确定CD8⁺FoxP3⁺免疫细胞是一种具有强大生物标志物潜力且不依赖癌种的细胞类型。

查看英文原文 English abstract

Immune infiltration shapes anti-tumor responses and is associated with patient outcomes. Yet, comprehensive studies comparing infiltration patterns and their clinical impact across cancer types are scarce.We profiled the tumor immune microenvironment across 16 solid tumor types from more than 2,700 patients using multiplex immunofluorescence with pathologist-curated image analysis to quantify major lymphoid and myeloid subsets and their spatial organization in situ.Across all cancer types, lung, endometrial, and high-grade serous ovarian cancers were highly infiltrated, whereas prostate and ER-positive breast cancers were comparatively “immune cold”. Cancer-agnostic consensus clustering resolved four reproducible immune archetypes with distinct outcomes, including an immune-hot group enriched for CD4, CD8, and B cells that associated with the best survival (p<0.001). Notably, the tumor type accounted for only a part of the immune contexture, as most cancers spanned multiple immune signature groups. Nevertheless, a machine-learning classifier trained on immune compositions distinguished tumor types with high accuracy (AUC = 0.96), confirming that each cancer maintains a recognizable immune imprint even among pan-cancer archetypes.Analysis of survival associations of individual cell classes revealed a rare CD8⁺FOXP3⁺ T-cell phenotype that emerged as a strongest positive prognostic factor across cancers (HR=0.79, 95%CI:[0.70-0.89], p=0.002). Single-cell RNA sequencing data indicated that CD8⁺FoxP3⁺ cells exhibit two distinct gene programs, with regulatory and cytotoxic capacities. Spatial mapping suggested context-dependency in the function of CD8⁺FoxP3⁺ cells, as their proximity to CD8 T cells was linked to better survival (enrichment at 10um: HR=0.76, 95%CI:[0.67-0.90], p=0.0006), whereas proximity to tumor cells was associated with worse prognosis (enrichment at 10um: HR=1.29, 95%CI:[1.12-1.49], p=0.0005).Together, our findings define pan-cancer immune archetypes that are both shared and disease-specific, explaining why “immune hot” and “cold” states are not synonymous with pure infiltration quantities. We identified CD8⁺FoxP3⁺ immune cells as a cell type with strong biomarker potential independent of cancer type.

利益披露 Disclosure

A. Mezheyeuski, None.. M. Backman, None.. A. T. Kahraman, None.. A. Lindberg, None.. C. Strell, None.. H. Brunnström, None.. J. Huvila, None.. M. Sund, None.. F. Wärnberg, None.. B. Glimelius, None.. I. Hrynchyk, None.. S. Mauchanski, None.. S. Khelashvili, None.. K. Hammarström, None.. M. Agnarsdottir, None.. G. Garcia-Vicién, None.. D. G. Mollevi, None.. A. O´Reilly, None.. S. Corvigno, None.. H. Dahlstrand, None.. J. Botling, None.. U. Segersten, None.. A. Krzyzanowska, None.. A. Bjartell, None.. J. Elebro, None.. M. Heby, None.. S. Lundgren, None.. C. Hedner, None.. D. Borg, None.. J. Brändstedt, None.. H. Sartor, None.. P. Malmström, None.. M. Johansson, None.. A. Portyanko, None.. B. Nodin, None.. C. Lindskog, None.. K. Leandersson, None.. K. Jirström, None.. T. Sjöblom, None.. P. Micke, None.

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