PO.TB10.01 · 肿瘤生物学

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

查看完整资料下载 PDF 登录后可访问当前开放资料 AACR 官方页面 ↗

作者与单位

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

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 ).

在会议检索中打开