PO.IM01.11 · 免疫学

肿瘤IL-33/ST2信号通过减少抗原呈递驱动免疫逃逸

Tumoral IL-33/ST2 signaling drives immune escape through reduced antigen presentation

编号 2799 展板 4 时间 4/20 02:00–05:00 区域 Section 7 主讲 Alyssa Mauri Cornista, AA;BS

分会场 Immune Checkpoints

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作者与单位 Authors & Affiliations

Alyssa Mauri Cornista¹, Tao Yu², Zhuolong Zhou², Nikša Roki¹, Alberto Sigler¹, David M. Suissa¹, Haniyeh Eyvani³, George E. Sandusky⁴, Rimpi Khurana⁵, Yan Guo⁶, Molly Dalzell¹, Shyamananda Singh Mayengbam⁷, Prasenjit Dey⁷, Christine Rafie¹, Erietta Stelekati⁸, Jashodeep Datta⁹, Saratchandra S. Khumukcham¹⁰, Jatin Roper¹⁰, Nivedh Paluvoi¹¹, Sandro Satta¹², Daniel Bilbao Cortes¹², Alejandro Villarino⁸, Kevin Van der Jeught⁸

¹Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL,²Medical and Molecular Genetics; Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN,³Medical and Molecular Genetics, University of Miami Miller School of Medicine, Miami, FL,⁴Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN,⁵Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL,⁶Sylvester Comprehensive Cancer Center; Public Health and Sciences, University of Miami Miller School of Medicine, Miami, FL,⁷Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY,⁸Microbiology and Immunology; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL,⁹Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL,¹⁰Medicine, Division of Gastroenterology; Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC,¹¹Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL,¹²Sylvester Comprehensive Cancer Center; Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL

摘要 Abstract

中文摘要

大多数（高达85%）结直肠癌（CRC）患者具有微卫星稳定（MSS）肿瘤表型，对免疫检查点阻断（ICB）反应不佳。因此，需要在肿瘤微环境中鉴定新的检查点，如ST2（Stimulation 2，IL33受体）。我们通过对CRC患者样本的多重免疫荧光染色和公开可用数据集，证明ST2在人肿瘤细胞上显著表达，尤其是MSS肿瘤。使用CRC患者来源的类器官，我们确定肿瘤IL33/ST2信号的激活赋予肿瘤细胞抵抗T细胞介导杀伤的保护。为研究肿瘤细胞逃避T细胞杀伤的机制基础，我们使用结肠镜诱导的原位小鼠肿瘤。我们发现IL33/ST2信号减少了抗原呈递，这是由免疫蛋白酶体活性降低所驱动的。使用CRISPR/Cas9基因编辑去除肿瘤ST2信号导致显著的肿瘤生长控制，并增加了具有较少终末耗竭表型的T细胞浸润。总之，这些发现表明ST2是肿瘤细胞上一个潜在的新型检查点靶点，可扩大从ICB中获益的患者群体。

查看英文原文 English abstract

The majority (up to 85%) of colorectal cancer (CRC) patients have a microsatellite stable (MSS) tumor phenotype, which is a poor responder to immune checkpoint blockade (ICB). Therefore, there is a need to identify novel checkpoints in the tumor microenvironment, such as ST2 (Stimulation 2, IL33 receptor). We demonstrated ST2 to be prominently expressed on human tumor cells, especially MSS tumors, through multiplex immunofluorescence staining of CRC patient samples and publicly available datasets. Using CRC patient-derived organoids, we established that activation of tumoral IL33/ST2 signaling conferred tumor cell protection from T cell-mediated killing. To investigate the mechanistic basis of how tumor cells escape T cell killing, we used colonoscopy-induced, orthotopic murine tumors. We uncovered that IL33/ST2 signaling reduced antigen presentation, driven by reduced immunoproteasome activity. Removing tumoral ST2 signaling using CRISPR/Cas9-gene editing leads to significant tumor growth control and increased infiltration of T cells with a reduced terminally exhausted phenotype. Altogether, these findings indicate ST2 as a potential, novel checkpoint target on tumor cells to enlarge the pool of patients benefiting from ICB.

利益披露 Disclosure

A. Cornista, None.. T. Yu, None.. Z. Zhou, None.. N. Roki, None.. A. Sigler, None.. D. M. Suissa, None.. H. Eyvani, None.. G. E. Sandusky, None.. R. Khurana, None.. Y. Guo, None.. M. Dalzell, None.. S. S. Mayengbam, None.. P. Dey, None.. C. Rafie, None.. E. Stelekati, None.. J. Datta, None.. S. S. Khumukcham, None.. J. Roper, None.. N. Paluvoi, None.. S. Satta, None.. D. Bilbao Cortes, None.. A. Villarino, None.. K. Van der Jeught, None.

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