PO.IM02.05 · 免疫学

肿瘤细胞CEBPB表达促成微卫星稳定型结直肠癌的T细胞介导免疫逃逸

Tumor cell CEBPB expression contributes to T cell-mediated immune evasion of microsatellite stable colorectal cancer

编号 7005 展板 17 时间 4/22 09:00–12:00 区域 Section 9 主讲 Hye Jeong Yun, PhD

分会场 Tumor-induced Immune Suppression

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作者与单位 Authors & Affiliations

Hye Jeong Yun¹, Chan Ho Park², Dahye Yun¹, Hye-Ri Shin³, Naeun Park¹, Changhee Park⁴, Jeong Dong Lee¹, Kiyeon Kim², Heejun Shim², Hyejin Sim¹, Se Min Kim¹, Min Jung Kim⁵, Ji Won Park⁵, Seung-Bum Ryoo⁵, Yoojoo Lim⁶, Seung-Yong Jeong⁵, Kyu Joo Park⁵, Tae-You Kim⁴, Junil Kim², Jae-Kyung Won³, Sae-Won Han⁴

¹Cancer Research Institute, Seoul National University Hospital, Seoul, Korea, Republic of,²Department of Bioinformatics, Soongsil University, Seoul, Korea, Republic of,³Department of Pathology, Seoul National University Hospital, Seoul, Korea, Republic of,⁴Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of,⁵Department of Surgery, Seoul National University Hospital, Seoul, Korea, Republic of,⁶Lunit, Seoul, Korea, Republic of

摘要 Abstract

中文摘要

背景：微卫星稳定（MSS）结直肠癌（CRC）约占所有结直肠癌病例的80-85%，对免疫检查点抑制剂应答不佳。肿瘤蛋白53（TP53）突变在结直肠癌中常见，可能促成肿瘤驱动的免疫抑制。本研究中，我们旨在探究MSS CRC中与TP53突变相关的免疫抑制机制。方法：我们对来自30例CRC患者的肿瘤样本以及同基因小鼠中Trp53敲除（KO）的CT26肿瘤进行了单细胞RNA测序（scRNA-seq），以刻画肿瘤微环境并基于TP53突变状态分析肿瘤细胞基因表达谱。我们鉴定出CCAAT增强子结合蛋白beta（CEBPB）为与TP53突变型CRC相关的潜在免疫抑制因子。为阐明CEBPB在T细胞免疫抑制中的作用，我们通过流式细胞术分析了T细胞-肿瘤细胞共培养以及注射CEBPB过表达（oe）肿瘤的同基因小鼠模型。结果：对30例CRC的scRNA-seq分析显示，TP53突变型肿瘤中CD4+ T细胞亚群（包括Treg、Th17和Tcm细胞）的比例增加。与TP53野生型肿瘤相比，免疫激活通路（如免疫系统和干扰素gamma应答）在T细胞中下调，提示TP53突变可能通过负面影响T细胞而促成免疫逃逸。对Trp53-KO CT26肿瘤的scRNA-seq分析鉴定出CEBPB显著上调，我们证实Trp53 WT的缺失导致CRC细胞系中CEBPB mRNA表达和蛋白稳定性增加。CEBPB表达与CD4+ T细胞浸润减少相关，并与调节性T细胞（Treg）和耗竭性T细胞（Tex）中细胞毒性T淋巴细胞相关蛋白4（CTLA4）表达呈正相关。同基因小鼠中的CEBPB-oe CT26肿瘤在体内显示CD4+ T细胞浸润减少以及CD4+ T细胞上CTLA-4表达上调。与此一致，与CEBPB过表达CT26细胞共培养的脾脏T细胞显示CTLA-4表达增加以及CD4+ T细胞增殖减少。结论：由TP53突变上调的肿瘤细胞CEBPB表达可能介导T细胞介导的免疫抑制，被认为是调控MSS CRC免疫逃逸的潜在治疗靶点。

查看英文原文 English abstract

Background: Microsatellite stable (MSS) colorectal cancer (CRC), which accounts for approximately 80-85% of all colorectal cancer cases, exhibits a poor response to immune checkpoint inhibitors. Tumor protein 53 ( TP53 ) mutations are frequently observed in colorectal cancer and may contribute to tumor-driven immunosuppression. In this study, we aimed to investigate the immunosuppressive mechanisms associated with TP53 mutations in MSS CRC. Methods: We performed single-cell RNA sequencing (scRNA-seq) on tumor samples from 30 CRC patients and Trp53 - knockout (KO) CT26 tumors in syngeneic mice to profile the tumor microenvironment and analyze tumor cell gene expression profiles based on TP53 mutation status. We identified CCAAT enhancer-binding protein beta ( CEBPB ) as a potential immunosuppressive factor associated with TP53 -mutant CRC. To demonstrate the role of CEBPB in T cell immunosuppression, we analyzed T cell-tumor cell co-cultures and CEBPB -overexpressing (oe) tumor-injected syngeneic mouse models by flow cytometry. Results: scRNA-seq analysis of 30 CRCs revealed increased proportions of CD4 + T cell subsets, including Treg, Th17, and Tcm cells, in TP53 mutant tumors. Immune activation pathways, such as the immune system and interferon-gamma response, were down-regulated in T cells compared to TP53 wild-type tumors, suggesting that TP53 mutations might contribute to immune evasion by negatively affecting T cells. scRNA-seq analysis of Trp53 -KO CT26 tumors identified CEBPB as notably upregulated, and we confirmed that loss of Trp53 WT led to increased CEBPB mRNA expression and protein stability in CRC cell lines. CEBPB expression was associated with reduced CD4 + T cell infiltration and positively correlated with cytotoxic T lymphocyte-associated protein 4 ( CTLA4 ) expression in regulatory T cells (Treg) and exhausted T cells (Tex). CEBPB -oe CT26 tumors in syngeneic mice showed reduced CD4 + T cell infiltration and upregulation of CTLA-4 expression on CD4 + T cells in vivo . Consistently, spleen T co-cultured with CEBPB -overexpressing CT26 cells showed increased CTLA-4 expression and decreased proliferation of CD4⁺ T cells. Conclusion: Tumor cell CEBPB expression, upregulated by TP53 mutation, may mediate T cell-mediated immunosuppression and is considered as potential therapeutic target for regulating immune evasion in MSS CRC.

利益披露 Disclosure

H. Yun, None.. C. Park, None.. D. Yun, None.. H. Shin, None.. N. Park, None.. C. Park, None.. J. Lee, None.. K. Kim, None.. H. Shim, None.. H. Sim, None.. S. Kim, None.. M. Kim, None.. J. Park, None.. S. Ryoo, None. Y. Lim, Lunit Employment. S. Jeong, None.. K. Park, None.. T. Kim, None.. J. Kim, None.. J. Won, None. S. Han, Arcus Biosciences ). AstraZeneca ). BeyondBio ). Eli Lilly and Company ). GC Biopharma ). Genentech ). Hanmi pharmaceutical ). IMBdx ). Janssen Pharmaceuticals ). Jeil Pharmaceutical Co. ). Jiangsu Hengrui Pharmaceuticals Co. ). Leap Therapeutics ). Loxo Oncology, Inc. ). MedImmune, LLC ). MSD ). Roche ). Seagen Inc. ). Turnstone Biologics ). Ono Pharmaceutical ). boryung biopharma ).

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