Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy.

By Yao Liu, Z. Xun, Kun Ma, Shuhang Liang, Xianying Li, Shuo Zhou, Linmao Sun, Yufeng Liu, Yanhua Du, Xinyu Guo and 16 more. Journal of Hepatology, 2023

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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 of the previous studies 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 (ST) with single-cell RNA sequencing (scRNA-seq) and multiplexed immunofluorescence of anti-PD-1-treated hepatocellular carcinoma (HCC) patients to reveal specific spatial structures in the TME related to immunotherapy efficacy. RESULTS We revealed the 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 (ICB) treatment. 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 ICB treatment in HCC. IMPACT AND IMPLICATIONS Only a limited number of patients with HCC benefit from tumour immunotherapy, which significantly hinders the application of immunotherapy in HCC patients. Here, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and CAFs in the HCC microenvironment and contributes to immunotherapy efficacy by limiting immune cell infiltration into malignant regions. Preclinically, we revealed that blocking SPP1 or macrophage-specific deletion of Spp1 in mice could destroy the TIB structure and sensitize HCC cells to immunotherapy. These results provide the first key steps towards finding more effective therapies for HCC and have a strong impact on physicians, scientists, and drug developers in the field of HCC.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/b21a517758074f5a82687f396c6fcba1d3a9c42b