PO.CL01.06 · 临床研究

胰腺导管腺癌中肿瘤内在性MHC-II激活增强免疫应答和治疗疗效

Tumor-intrinsic MHC-II activation in pancreatic ductal adenocarcinoma enhances immune response and treatment efficacy

编号 7716 展板 7 时间 4/22 09:00–12:00 区域 Section 41 主讲 Canping Chen, MS

分会场 Biomarkers Predictive of Therapeutic Benefit 6

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作者与单位 Authors & Affiliations

Canping Chen¹, Kyle P. Gribbin², Xi Li³, Tugba Ozmen⁴, Furkan Ozmen⁴, Shamilene Sivagnanam², James Kim², Katie E. Blise⁵, Xinxing Yang¹, Yi Zhang², Dove Keith⁵, Mara H. Sherman⁶, Mushui Dai⁷, Lisa M. Coussens⁸, Charles D. Lopez⁹, Rosalie C. Sears⁷, Gordon B. Mills¹⁰, Katelyn T. Byrne⁷, Zheng Xia¹⁰

¹Biomedical Engineer, Oregon Health & Science University, Portland, OR,²Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR,³Medical, Huazhong University of Science and Technology, Wuhan, China,⁴Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR,⁵Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR,⁶Memorial Sloan Kettering Cancer Center, New York, NY,⁷OHSU, Portland, OR,⁸OHSU Knight Cancer Institute, Lake Oswego, OR,⁹Assoc. Professor, Div. of Hemat./Onc., Oregon Health & Science University, Portland, OR,¹⁰OHSU Knight Cancer Institute, Portland, OR

摘要 Abstract

中文摘要

胰腺导管腺癌（PDAC）以免疫抑制性肿瘤微环境（TME）和不良预后为特征。虽然主要组织相容性复合体II类（MHC-II）表达传统上与专职抗原呈递细胞相关，但其在PDAC恶性细胞中的作用仍未得到充分研究。在此，我们利用单细胞RNA测序（scRNA-seq）、空间转录组学、bulk RNA测序、多重免疫组织化学（mIHC）以及使用人源和鼠源模型的离体培养研究，探讨了MHC-II表达在恶性PDAC细胞中的预后相关性。恶性细胞中MHC-II表达升高与人PDAC中CD4+ T细胞和CD8+ T细胞浸润增加密切相关，并与浆细胞显著共定位，提示一种抗原激活的免疫微环境。在PDAC的KPC小鼠模型中，通过cobimetinib治疗在恶性上皮细胞中药理学诱导MHC-II表达，可显著增强对免疫检查点阻断（ICB）的治疗应答。这些发现凸显了恶性细胞内在性MHC-II表达在促进抗原呈递和构建抗肿瘤免疫微环境中的作用。我们的结果将MHC-II定位为PDAC中一种有前景的预后生物标志物和治疗靶点，为新型免疫调节策略铺平了道路。

查看英文原文 English abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressivetumor microenvironment (TME) and poor prognosis. While major histocompatibility complexclass II (MHC-II) expression is traditionally associated with professional antigen-presentingcells, its role in PDAC malignant cells remains underexplored. Herein, we utilized single-cellRNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA sequencing, multipleximmunohistochemistry (mIHC) and ex vivo studies in culture with both human and murinemodels to investigate the prognostic relevance of MHC-II expression in malignant PDACcells. Elevated MHC-II expression in malignant cells was strongly associated with increasedinfiltration of CD4+ T and CD8+ T cells in human PDAC, and pronounced co-localization withplasma cells, indicative of an antigen-activated immune microenvironment. In the KPCmouse model of PDAC, pharmacologic induction of MHC-II expression by cobimetinibtreatment in malignant epithelial cells significantly enhanced the therapeutic response toimmune checkpoint blockade (ICB). These findings highlight the role of malignant cell-intrinsic MHC-II expression in promoting antigen presentation and fostering an anti-tumorimmune microenvironment. Our results position MHC-II as a promising prognostic biomarkerand therapeutic target in PDAC, paving the way for novel immunomodulatory strategies.

利益披露 Disclosure

C. Chen, None.. K. P. Gribbin, None.. X. Li, None.. T. Ozmen, None.. F. Ozmen, None.. S. Sivagnanam, None.. J. Kim, None.. K. E. Blise, None.. X. Yang, None.. Y. Zhang, None.. D. Keith, None.. Z. Xia, None.

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