TREM2+macrophages suppress CD8+T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma
TREM2+macrophages suppress CD8+T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma
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DOI：
10.1016/j.jhep.2023.02.032
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发表时间：
2023-06-15
影响因子：
25.7
通讯作者：
Li, Jiaping
中科院分区：
文献类型：
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作者：
Tan, Jizhou;Fan, Wenzhe;Li, Jiaping
背景与目的：肝细胞癌（HCC）经动脉化疗栓塞（TACE）后的免疫状况仍有待澄清。本研究旨在阐明TACE后的免疫景观和HCC progression.Methods的潜在机制：从5例未经治疗的HCC患者和5例接受TACE治疗的患者收集肿瘤样本，并进行单细胞RNA测序。另外22个配对样本用免疫荧光染色和流式细胞术进行验证。为了阐明潜在的机制，在体外共培养实验和两种类型的TREM 2-KO/ WT小鼠模型，即肝癌细胞原位注射模型和自发性HCC模型，used.Results：减少数量的CD 8 + T细胞和增加数量的肿瘤相关巨噬细胞（TAMs）中观察到TACE后的微环境。TACE治疗减少了簇CD8_C4，其高度富集了预先耗尽表型的肿瘤特异性CD 8 + T细胞。发现TREM 2在TACE后的TAM中高度表达，这与不良预后相关。与TREM 2-TAM相比，TREM 2 + TAM分泌较少的CXCL 9，但分泌较多的半乳糖凝集素-1。Galectin-1促进血管内皮细胞中PD-L1的过表达，阻碍CD 8 + T细胞的募集。TREM 2缺陷还增加了CD 8 + T细胞浸润，这在两种体内HCC模型中抑制了肿瘤生长。更重要的是，TREM 2缺陷增强了抗PD-L1阻断的治疗效果。结论：本研究表明TREM 2 + TAM在抑制CD 8 + T细胞中起重要作用。TREM 2缺陷通过增强CD 8 + T细胞的抗肿瘤活性来增加抗PD-L1阻断的治疗效果。这些研究结果解释了TACE后复发和进展的原因，并提供了一个新的靶点肝癌免疫治疗后TACE.Impact和Implications：研究免疫景观在TACE后肝癌是重要的，以揭示肝癌进展的机制。通过使用scRNA测序和功能测定，我们发现CD 8 + T细胞的数量和功能都受到损害，而TREM 2 + TAM的数量在TACE后HCC中增加，与预后较差相关。此外，TREM 2缺陷显著增加CD 8 + T细胞浸润并增强抗PD-L1阻断的治疗功效。在机制上，TREM 2 + TAM显示出比TREM 2-TAM更低的CXCL 9和增加的Gal-1分泌，其中Gal-1介导血管内皮细胞中PD-L1的过表达。这些结果表明，TREM 2可能是HCC患者TACE治疗的新免疫靶点。这提供了打破有限治疗效果的平台期的机会。本研究对于了解TACE后肝癌的肿瘤微环境，为肝癌的免疫治疗提供新的思路具有重要价值。因此，它对肝癌和胃肠道肿瘤领域的医生，科学家和药物开发人员具有关键影响。COPY; 2023欧洲肝脏研究协会Elsevier B. V.出版，保留所有权利。
Background & Aims: The immune landscape of hepatocellular carcinoma (HCC) following transarterial chemoembolisation (TACE) remains to be clarified. This study aimed to characterise the immune landscape following TACE and the underlying mechanism of HCC progression.Methods: Tumour samples from five patients with treatment-naive HCC and five patients who received TACE therapy were collected and subjected to single-cell RNA sequencing. Another 22 paired samples were validated using immunofluorescence staining and flow cytometry. To clarify the underlying mechanisms, in vitro co-culture experiments and two types of TREM2-KO/ WT mouse models, namely, an HCC cell orthotopic injection model and a spontaneous HCC model, were used.Results: A reduced number of CD8+ T cells and an increased number of tumour-associated macrophages (TAMs) were observed in the post-TACE microenvironment. TACE therapy reduced the cluster CD8_C4, which was highly enriched with tumour-specific CD8+ T cells of pre-exhausted phenotype. TREM2 was found to be highly expressed in TAMs following TACE, which was associated with a poor prognosis. TREM2+ TAMs secreted less CXCL9 but more galectin-1 than did TREM2- TAMs. Galectin-1 promoted PD-L1 overexpression in vessel endothelial cells, impeding CD8+ T cell recruitment. TREM2 deficiency also increased CD8+ T cell infiltration, which inhibited tumour growth in both in vivo HCC models. More importantly, TREM2 deficiency enhanced the therapeutic effect of anti-PD-L1 blockade.Conclusions: This study shows that TREM2+ TAMs play an important role in suppressing CD8+ T cells. TREM2 deficiency increased the therapeutic effect of anti-PD-L1 blockade by enhancing antitumour activity of CD8+ T cells. These findings explain the reasons for recurrence and progression after TACE and provide a new target for HCC immunotherapy after TACE.Impact and Implications: Studying the immune landscape in post-TACE HCC is important to uncover the mechanisms of HCC progression. By using scRNA sequencing and functional assays, we discovered that both the number and function of CD8+ T cells are compromised, whereas the number of TREM2+ TAMs is increased in post-TACE HCC, correlating with worse prognosis. Moreover, TREM2 deficiency dramatically increases CD8+ T cell infiltration and augments the therapeutic efficacy of anti-PD-L1 blockade. Mechanistically, TREM2+ TAMs display lower CXCL9 and increased Gal-1 secretion than do TREM2- TAMs, with Gal-1 mediating the overexpression of PD-L1 in vessel endothelial cells. These results suggest that TREM2 could be a novel immunotherapeutic target for patients treated with TACE in HCC. This provides an opportunity to break the plateau of limited therapeutic effect. This study has the value of understanding the tumour microenvironment of post-TACE HCC and thinking a new strategy of immunotherapy in the field of HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology.& COPY; 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.