PO.TB10.02 · 肿瘤生物学

免疫调节性PIGR+RORC+树突状细胞（PRDC）在恶性腹水中富集

Immunomodulatory PIGR + RORC + dendritic cells (PRDCs) are enriched in malignant ascites

编号 6134 展板 25 时间 4/21 02:00–05:00 区域 Section 28 主讲 Steven Blum, MD

分会场 Metastasis and Organ-Specific Microenvironmental Evolution

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作者与单位 Authors & Affiliations

Steven M. Blum¹, Thomas L. Chan¹, Neal P. Smith¹, Courtney Ambrose¹, Katherine H. Xu¹, Alice Tirard¹, Nandini Samanta¹, Sidney Martin¹, Roya Best¹, Elizabeth Tuttle¹, Christopher T. Stueber¹, Vaishnavi R. Yalala¹, Haley Barnes¹, Sean T. Bannon¹, Yuhui Song¹, Benjamin Y. Arnold¹, Mushriq Al-Jazrawe², Joseph J. Zhao³, Kamil Slowikowski¹, Jessica Tantivit¹, Kasidet Manakongtreecheep¹, Lukas M. Altenburger¹, Simon Knott⁴, Matthew R. Strickland¹, Michael G. Drage¹, Linda T. Nieman¹, Jesse S. Boehm², Raghav Sundar⁵, Gary Reynolds¹, Samuel J. Klempner¹, Alexandra-Chloé Villani¹

¹Massachusetts General Hospital, Boston, MA,²Koch Inst. for Integrative Cancer Research at MIT, Cambridge, MA,³Yong Loo Lin School of Medicine, Singapore, Singapore,⁴Cedars-Sinai Medical Center, Los Angeles, CA,⁵Yale University School of Medicine, New Haven, CT

摘要 Abstract

中文摘要

背景：腹膜癌病和恶性腹水常由实体瘤引起，腹水的存在与预后不良及对免疫检查点抑制剂的抵抗相关。虽然已有关于腹水某些免疫抑制特征的描述，但树突状细胞（DC）亚群在这一微环境中的作用尚不清楚。近期，在正常小鼠和人组织中发现了一种表达RORC的DC亚群，它们与对肠道抗原的耐受相关。然而，这一DC群体此前未与癌症相关联，也未在人类中得到充分表征。方法：我们对来自胃癌和胃食管腺癌（GEA；共523,322个细胞）患者的腹水（n=23）和配对外周血（n=15）进行了单细胞RNA测序（scRNA-seq）联合配对表面蛋白质组学（CITE-seq）以及分泌蛋白质组学（n=109种分析物）。使用来自GEA和胰腺癌伴腹水患者的DC进行同种异体混合淋巴细胞反应（MLR）。体外分化实验利用来自健康供者的cDC，将其培养于补充有腹水上清液或GEA患者配对血浆的培养基中。结果：我们鉴定出一个表达PIGR和RORC的DC亚群（PRDC），它们在转录上与经典DC亚群不同，而与耐受性细胞亚群相似。对公开数据集中>1×10^7个细胞的分析提示，PRDC存在于其他人组织中，但在GEA和卵巢癌的恶性腹水中富集。分选的PRDC在MLR中刺激T细胞增殖。然而，对由PRDC刺激的T细胞进行的scRNA-seq显示，与由cDC2刺激的T细胞相比，这些T细胞因效应细胞因子基因（例如IFNG、IL5、IL13）表达降低而极化效率较低。空间转录组学证实了人淋巴组织中存在PRDC样细胞，邻近的增殖性CD4 T细胞同样表现出极化特征降低。通过将健康供者血液来源的cDC1培养于恶性腹水患者的上清液中，可诱导出PRDC转录程序的特征，提示PRDC是在腹水微环境中被诱导产生的。结论：PRDC代表一种保守的、免疫调节性的DC亚群，在恶性腹水中富集。PRDC能够调节T细胞反应，可能代表由腹水微环境诱导的一种耐受性状态。靶向PRDC或其分化通路可能为增强腹膜转移患者的抗肿瘤免疫提供新策略。

查看英文原文 English abstract

Background : Peritoneal carcinomatosis and malignant ascites are frequently caused by solid tumors, and the presence of ascites is associated with a poor prognosis and resistance to immune checkpoint inhibitors. While some immunosuppressive features of ascites have been described, the role of dendritic cell (DC) subsets in this microenvironment is unknown. Recently, a subset of DCs that express RORC have been found in normal mouse and human tissues, and they have been linked to tolerance of gut antigens. However, this DC population has not previously been associated with cancer or well characterized in humans. Methods : We performed single-cell RNA sequencing (scRNA-seq) with paired surface proteomics (CITE-seq), and secreted proteomics (n = 109 analytes) on ascites (n = 23) and matched peripheral blood (n = 15) from patients with gastric and gastroesophageal adenocarcinoma (GEA; n = 523,322 total cells). Allogeneic mixed lymphocyte reactions (MLRs) were performed using DCs from GEA and pancreas cancer patients with ascites. In vitro differentiation experiments leveraged cDCs from healthy donors and cultured them in media supplemented with ascites supernatant or paired plasma from GEA patients. Results : We identified a DC subset expressing PIGR and RORC (PRDCs) that were transcriptionally distinct from canonical DC subsets and similar to tolerogenic cell subsets. Analysis of >1x10 7 cells from public datasets suggest that PRDCs are found in other human tissues but enriched in malignant ascites from both GEA and ovarian cancers. Sorted PRDCs stimulated T-cell proliferation in MLRs. However, scRNAseq of T cells stimulated by PRDCs showed that those T cells were less effectively polarized due to reduced expression of effector cytokine genes ( e.g. , IFNG , IL5 , IL13 ) compared to T cells stimulated by cDC2s. Spatial transcriptomics confirmed the presence of PRDC-like cells in human lymphoid tissues, and neighboring, proliferating CD4 T cells similarly showed reduced polarization signatures. Features of the PRDC transcriptional program could be induced by culturing blood-derived cDC1s from healthy donors in supernatant from patients with malignant ascites, suggesting that PRDCs are induced in the ascites microenvironment. Conclusions : PRDCs represent a conserved, immunomodulatory DC subset enriched in malignant ascites. PRDCs are capable of modulating T-cell responses and may represent a tolerogenic state induced by the ascites microenvironment. Targeting PRDCs or their differentiation pathways may offer new strategies to enhance anti-tumor immunity in patients with peritoneal metastases.

利益披露 Disclosure

S. M. Blum, None.. T. L. Chan, None.. N. P. Smith, None.. C. Ambrose, None.. K. H. Xu, None.. A. Tirard, None.. N. Samanta, None.. S. Martin, None.. R. Best, None.. E. Tuttle, None.. C. T. Stueber, None.. V. R. Yalala, None.. H. Barnes, None.. S. T. Bannon, None.. Y. Song, None.. B. Y. Arnold, None.. M. Al-Jazrawe, None.. J. J. Zhao, None.. K. Slowikowski, None.. J. Tantivit, None.. K. Manakongtreecheep, None.. L. M. Altenburger, None.. S. Knott, None. M. R. Strickland, Astellas Pharma Independent Contractor. Bristol Myers Squibb Independent Contractor. AstraZeneca Independent Contractor. M. G. Drage, None.. L. T. Nieman, None.. J. S. Boehm, None. R. Sundar, Bristol Myers Squibb ). Merck ). Eisai ). Bayer ). Taiho ). Novartis ). Eli Lilly ). Roche ). AstraZeneca ). Paxman Coolers ). Merck Sharp & Dohme ). Natera ). Astellas ). GlaxoSmithKline ). Ipsen ). Pierre - Fabre ). Tavotek ). Sanofi ). Daichii Sankyo ). Beigene ). G. Reynolds, None. S. J. Klempner, Astellas Independent Contractor. Merck Independent Contractor. AstraZeneca Independent Contractor. Gilead Independent Contractor. Eisai Independent Contractor. Taiho Oncology Independent Contractor. Daiichi - Sankyo Independent Contractor. Amgen Independent Contractor. A. Villani, Bristol Myers Squibb Independent Contractor. Merck Independent Contractor.

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