PO.TB10.01 · 肿瘤生物学

与普通型间质性肺炎相关的肺腺癌的二分性免疫遗传学图谱

Dichotomous immunogenetic landscape of lung adenocarcinoma associated with usual interstitial pneumonia

编号 2272 展板 21 时间 4/20 09:00–12:00 区域 Section 33 主讲 Akifumi Mochizuki, MD;PhD

分会场 Tumorigenesis and Early Microenvironmental Trajectories

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作者与单位 Authors & Affiliations

Akifumi Mochizuki¹, Ayako Suzuki², Kouya Shiraishi³, Masahiro Torasawa⁴, Takayuki Honda¹, Susumu Kirimura⁵, Yasunari Miyazaki¹, Kenichi Okubo⁶, Syuzo Kaneko⁷, Yukihiro Yoshida⁸, Shun-ichi Watanabe⁸, Masahiro Tsuboi⁹, Genichiro Ishii¹⁰, Issei Imoto¹¹, Ryuji Hamamoto¹², Yasushi Yatabe¹³, Yutaka Suzuki², Takashi Kohno³

¹Department of Respiratory Medicine, Institute of Science Tokyo, Tokyo, Japan,²Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan,³National Cancer Center Research Institute, Tokyo, Japan,⁴Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan,⁵Division of Pathology, Institute of Science Tokyo, Tokyo, Japan,⁶Department of Thoracic Surgery, Institute of Science Tokyo, Tokyo, Japan,⁷Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan,⁸Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan,⁹Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan,¹⁰Department of Pathology and Clinical laboratories, National Cancer Center Hospital East, Kashiwa, Japan,¹¹Dept. of Human Genetics, Inst. of Health Biosciences, Aichi Cancer Center Research Institute, Nagoya, Japan,¹²Associate Professor, National Cancer Center Japan, Tokyo, Japan,¹³Chief, Dept. of Pathology & Molec. Diagnostics, National Cancer Center, Nagoya, Japan

摘要 Abstract

中文摘要

背景：间质性肺炎会增加肺癌风险；然而其潜在的致癌通路仍知之甚少。普通型间质性肺炎（UIP）常与肺腺癌（LADC）共定位，为理解慢性炎症驱动的癌变提供了模型。方法：我们对44例UIP(+) LADC进行了全基因组和RNA测序，并将其与216例UIP(-) LADC进行比较。为解决瘤内异质性并表征肿瘤微环境，我们使用全转录组平台（Visium，55 μm分辨率）和单细胞分辨率平台（Xenium肺部panel，302个基因；Xenium 5K，5,018个基因）进行了空间转录组学分析。结果：UIP(+) LADC表现出独特的分子特征：低肿瘤突变负荷、无EGFR突变，以及广泛存在的肌成纤维细胞型癌相关成纤维细胞（myCAFs），后者可能来源于UIP中的纤维化肌成纤维细胞。最常见的遗传学改变发生在NKX2-1（41%），该基因编码肺谱系转录因子TTF-1。观察到一种二分性免疫遗传学图谱：NKX2-1缺陷型肿瘤表现出胃肠道分化、频繁的ERBB2扩增伴超级增强子形成，以及免疫"冷"特征；NKX2-1充足型肿瘤则表现出免疫"热"特征，伴有丰富的瘤内CD8+ T细胞和升高的PD-L1表达。空间转录组学分析揭示了与NKX2-1表达状态相关的瘤内异质性，提示存在异常的胃肠道分化。此外，还鉴定出表达WNT5A和CTHRC1的myCAFs，其可能来源于UIP相关的肌成纤维细胞。配对的肿瘤与UIP区域显示，CTHRC1+WNT5A+ myCAF细胞群在肿瘤组织中相较于匹配的UIP区域显著富集，提示其在癌变过程中发生了扩增。结论：我们提出了一种由NKX2-1状态决定的UIP相关肺癌变双重模型，其中来源于UIP相关肌成纤维细胞的myCAFs驱动了两条致癌通路。这些发现基于二分性免疫遗传学图谱提供了靶向治疗策略，并强调靶向肌成纤维细胞向myCAF转变可作为慢性肺纤维化癌症预防的潜在途径。

查看英文原文 English abstract

Background: Interstitial pneumonia increases the risk of lung cancer; however, the underlying carcinogenic pathways remain poorly understood. Usual interstitial pneumonia (UIP) frequently co-localizes with lung adenocarcinoma (LADC), providing a model to understand chronic inflammation-driven carcinogenesis. Method: We conducted whole-genome and RNA sequence of 44 UIP (+) LADCs and compared them with 216 UIP (-) LADCs. To address intra-tumoral heterogeneity and characterize the tumor microenvironment, we performed spatial transcriptomics using a whole-transcriptome platform (Visium, 55 µm resolution) and single-cell-resolution platforms (Xenium lung panel, 302 genes; Xenium 5K, 5,018 genes). Results: UIP (+) LADCs exhibited unique molecular features: low tumor mutation burden, absence of EGFR mutations, and a pervasive presence of myofibroblastic cancer-associated fibroblasts (myCAFs), likely derived from fibrotic myofibroblasts in UIP. The most common genetic alteration was in NKX2-1 (41%), encoding the lung-lineage transcription factor TTF-1. A dichotomous immunogenetic landscape was observed: NKX2-1-deficient tumors showed gastrointestinal differentiation, frequent ERBB2 amplification with super-enhancer formation, and immune "cold" characteristics; NKX2-1-proficient tumors exhibited immune "hot" characteristics with abundant intra-tumoral CD8+ T cells and elevated PD-L1 expression. Spatial transcriptomics analysis revealed intratumor heterogeneity associated with NKX2-1 expression status, suggesting illegitimate gastrointestinal differentiation. In addition, the presence of WNT5A- and CTHRC1-expressing myCAFs were identified, which may originate from UIP-associated myofibroblasts. Paired tumor and UIP regions demonstrated that CTHRC1+WNT5A+ myCAF population was markedly enriched in tumor tissues relative to matched UIP regions, suggesting their expansion during carcinogenesis. Conclusion: We propose a dual model of UIP-associated lung carcinogenesis determined by NKX2-1 status, wherein myCAFs derived from UIP-associated myofibroblasts drive both carcinogenic pathways. These findings offer targeted therapeutic strategies based on the dichotomous immunogenetic landscape and highlight targeting the myofibroblast-to-myCAF transition as a potential approach for cancer prevention in chronic pulmonary fibrosis.

利益披露 Disclosure

A. Mochizuki, None.. A. Suzuki, None.. K. Shiraishi, None.. M. Torasawa, None.. T. Honda, None.. S. Kirimura, None.. Y. Miyazaki, None.. K. Okubo, None.. S. Kaneko, None.. Y. Yoshida, None.. S. Watanabe, None.. M. Tsuboi, None.. G. Ishii, None.. Y. Suzuki, None. T. Kohno, Thermo Fisher Scientific Patent. RIKEN Genesis Patent. Amoy Patent. Foundation Medicine Patent. Eli Lilly Japan Independent Contractor, ). Sysmex ). Chugai Pharmaceutical ). Konica Minolta ). Guardant Health ). Eurofins Clinical Genetics ).

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