Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy
Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy
复制标题
在肝细胞癌微环境中鉴定一种决定免疫疗法疗效的肿瘤免疫屏障
DOI：
10.1016/j.jhep.2023.01.011
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发表时间：
2023-03-15
影响因子：
25.7
通讯作者：
Liu, Lianxin
中科院分区：
文献类型：
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作者：
Liu, Yao;Xun, Zhenzhen;Liu, Lianxin
背景与目的：肿瘤微环境（TME）是癌症进展和治疗结果的重要介质。TME亚型与多种癌症中患者对免疫疗法的反应相关。大多数先前的研究都集中在与免疫治疗功效相关的TME中不同细胞组分的作用。然而，TME的具体结构及其在免疫治疗疗效中的作用在很大程度上仍然未知。方法：我们将空间转录组学与单细胞RNA测序和多重免疫荧光相结合，以确定TME中的特定空间结构，这些结构决定了接受抗PD-1治疗的肝细胞癌（HCC）患者的免疫治疗疗效。我们确定了肿瘤免疫屏障（TIB）结构，即由位于肿瘤边界附近的SPP 1+巨噬细胞和癌症相关成纤维细胞（CAF）组成的空间生态位，其与免疫检查点阻断的功效相关。此外，我们解剖了恶性细胞，SPP 1+巨噬细胞和CAFs之间的配体-受体网络;也就是说，缺氧微环境促进SPP 1表达，SPP 1+巨噬细胞与CAFs相互作用，刺激细胞外基质重塑，促进TIB结构形成，从而限制肿瘤核心的免疫浸润。临床前，SPP 1或Spp 1的巨噬细胞特异性缺失的小鼠中的封锁，导致抗PD-1治疗小鼠肝癌的疗效增强，伴随着减少CAF浸润和增加细胞毒性T细胞infiltration.Conclusions：我们确定了TIB结构形成的SPP 1+巨噬细胞和CAFs的相互作用与免疫治疗疗效。因此，通过阻断SPP 1破坏TIB结构可被认为是增强免疫检查点阻断在HCC中的治疗效果的相关治疗方法。(c)2023年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy. However, the specific structure of the TME and its role in immunotherapy efficacy remain largely unknown.Methods: We combined spatial transcriptomics with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the TME that determine the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 treatment.Results: We identified a tumour immune barrier (TIB) structure, a spatial niche composed of SPP1+ macrophages and cancer -associated fibroblasts (CAFs) located near the tumour boundary, which is associated with the efficacy of immune checkpoint blockade. Furthermore, we dissected ligand-receptor networks among malignant cells, SPP1+ macrophages, and CAFs; that is, the hypoxic microenvironment promotes SPP1 expression, and SPP1+ macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thereby limiting immune infiltration in the tumour core. Preclinically, the blockade of SPP1 or macrophage-specific deletion of Spp1 in mice led to enhanced efficacy of anti-PD-1 treatment in mouse liver cancer, accompanied by reduced CAF infiltration and increased cytotoxic T-cell infiltration.Conclusions: We identified that the TIB structure formed by the interaction of SPP1+ macrophages and CAFs is related to immunotherapy efficacy. Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC.(c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.