Journal of Hepatology ( IF 26.8 ) Pub Date : 2022-06-20 , DOI: 10.1016/j.jhep.2022.05.043 Giorgia Alvisi 1 , Alberto Termanini 2 , Cristiana Soldani 3 , Federica Portale 4 , Roberta Carriero 2 , Karolina Pilipow 1 , Guido Costa 5 , Michela Polidoro 3 , Barbara Franceschini 3 , Ines Malenica 3 , Simone Puccio 6 , Veronica Lise 7 , Giovanni Galletti 1 , Veronica Zanon 1 , Federico Simone Colombo 8 , Gabriele De Simone 8 , Michele Tufano 1 , Alessio Aghemo 9 , Luca Di Tommaso 10 , Clelia Peano 11 , Javier Cibella 12 , Matteo Iannacone 13 , Rahul Roychoudhuri 14 , Teresa Manzo 15 , Matteo Donadon 5 , Guido Torzilli 5 , Paolo Kunderfranco 2 , Diletta Di Mitri 16 , Enrico Lugli 1 , Ana Lleo 9
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Background & Aims
The landscape and function of the immune infiltrate of intrahepatic cholangiocarcinoma (iCCA), a rare, yet aggressive tumor of the biliary tract, remains poorly characterized, limiting development of successful immunotherapies. Herein, we aimed to define the molecular characteristics of tumor-infiltrating leukocytes with a special focus on CD4+ regulatory T cells (Tregs).
Methods
We used high-dimensional single-cell technologies to characterize the T-cell and myeloid compartments of iCCA tissues, comparing these with their tumor-free peritumoral and circulating counterparts. We further used genomics and cellular assays to define the iCCA-specific role of a novel transcription factor, mesenchyme homeobox 1 (MEOX1), in Treg biology.
Results
We found poor infiltration of putative tumor-specific CD39+ CD8+ T cells accompanied by abundant infiltration of hyperactivated CD4+ Tregs. Single-cell RNA-sequencing identified an altered network of transcription factors in iCCA-infiltrating compared to peritumoral T cells, suggesting reduced effector functions by tumor-infiltrating CD8+ T cells and enhanced immunosuppression by CD4+ Tregs. Specifically, we found that expression of MEOX1 was highly enriched in tumor-infiltrating Tregs, and demonstrated that MEOX1 overexpression is sufficient to reprogram circulating Tregs to acquire the transcriptional and epigenetic landscape of tumor-infiltrating Tregs. Accordingly, enrichment of the MEOX1-dependent gene program in Tregs was strongly associated with poor prognosis in a large cohort of patients with iCCA.
Conclusions
We observed abundant infiltration of hyperactivated CD4+ Tregs in iCCA tumors along with reduced CD8+ T-cell effector functions. Interfering with hyperactivated Tregs should be explored as an approach to enhance antitumor immunity in iCCA.
Lay summary
Immune cells have the potential to slow or halt the progression of tumors. However, some tumors, such as intrahepatic cholangiocarcinoma, are associated with very limited immune responses (and infiltration of cancer-targeting immune cells). Herein, we show that a specific population of regulatory T cells (a type of immune cell that actually suppresses the immune response) are hyperactivated in intrahepatic cholangiocarcinoma. Targeting these cells could enable cancer-targeting immune cells to act more effectively and should be looked at as a potential therapeutic approach to this aggressive cancer type.
中文翻译：
肝内胆管癌的多模式单细胞分析将过度活化的 Tregs 定义为潜在的治疗靶点
背景与目标
肝内胆管癌(iCCA) 是一种罕见但具有侵袭性的胆道肿瘤，其免疫浸润的景观和功能仍然缺乏特征，限制了成功免疫疗法的发展。在此，我们旨在确定肿瘤浸润性白细胞的分子特征，特别关注 CD4+ 调节性 T 细胞 (Tregs)。
方法
我们使用高维单细胞技术来表征 iCCA 组织的 T 细胞和骨髓隔室，并将其与无肿瘤的肿瘤周围和循环对应物进行比较。我们进一步使用基因组学和细胞分析来定义新型转录因子间充质同源框 1 (MEOX1) 在 Treg 生物学中的 iCCA 特异性作用。
结果
我们发现推定的肿瘤特异性 CD39+ CD8+ T 细胞浸润不良，伴有大量过度活化的 CD4+ Tregs 浸润。与肿瘤周围 T 细胞相比，单细胞 RNA 测序确定了 iCCA 浸润中转录因子网络的改变，表明肿瘤浸润 CD8+ T 细胞的效应功能降低，而 CD4+ Tregs 的免疫抑制作用增强。具体来说，我们发现 MEOX1 的表达在肿瘤浸润性 Tregs 中高度富集，并证明 MEOX1 过表达足以重编程循环 Tregs 以获得肿瘤浸润性 Tregs 的转录和表观遗传景观。因此，Tregs 中 MEOX1 依赖性基因程序的富集与大量 iCCA 患者的不良预后密切相关。
结论
我们观察到 iCCA 肿瘤中过度活化的 CD4+ Treg 大量浸润，同时 CD8+ T 细胞效应功能降低。应探索干扰过度活化的 Tregs 作为增强 iCCA 中抗肿瘤免疫的方法。
总结
免疫细胞有可能减缓或阻止肿瘤的进展。然而，一些肿瘤，如肝内胆管癌，与非常有限的免疫反应（以及靶向癌症的免疫细胞的浸润）有关。在这里，我们表明特定的调节性 T 细胞群（一种实际上抑制免疫反应的免疫细胞）在肝内胆管癌中被过度激活。靶向这些细胞可以使靶向癌症的免疫细胞更有效地发挥作用，应该将其视为这种侵袭性癌症类型的潜在治疗方法。
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