- •Integration of multi-omics was used to identify a TIB (tumour immune barrier) structure in the HCC microenvironment.
- •This TIB structure contributes to the efficacy of immunotherapy.
- •SPP1+ macrophages and CAFs interact to promote the formation of the TIB structure and limit immune infiltration of tumours.
- •Blockade of SPP1 or macrophage-specific deletion of Spp1 in mice can destroy the TIB structure and sensitize HCC to immunotherapy.
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.
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.
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.
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.
Impact and implications
Only a limited number of patients with hepatocellular carcinoma (HCC) benefit from tumour immunotherapy, which significantly hinders its application. Herein, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and cancer-associated fibroblasts in the HCC microenvironment. This structure constrains 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 implications for physicians, scientists, and drug developers in the field of HCC.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Hepatology
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Hepatocellular carcinoma.The Lancet. 2018; 391: 1301-1314
- Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.The Lancet. 2018; 391: 1163-1173
- Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.The Lancet. 2017; 389: 2492-2502
- A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.J Hepatol. 2013; 59: 81-88
- Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.New Engl J Med. 2020; 382: 1894-1905
- Comprehensive analysis of spatial architecture in primary liver cancer.Sci Adv. 2021; 7: 3750
- A human liver cell atlas reveals heterogeneity and epithelial progenitors.Nature. 2019; 572: 199-204
- Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in hepatocellular carcinoma.Cell. 2020; 183: 377-394.e21
- Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression.Cell Discov. 2020; 6: 1-15
- Landscape and dynamics of single immune cells in hepatocellular carcinoma.Cell. 2019; 179: 829-845.e20
- Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP.J Exp Clin Cancer Res. 2019; 38: 1-17
- Hepatic carcinoma-associated fibroblasts induce Ido-producing regulatory dendritic cells through il-6-mediated stat3 activation.Oncogenesis. 2016; 5 (e198–e198)
- Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells.Oncogene. 2017; 36: 1090-1101
- Conserved pan-cancer microenvironment subtypes predict response to immunotherapy.Cancer Cell. 2021; 39: 845-865.e7
- Fast, sensitive and accurate integration of single-cell data with Harmony.Nat Methods. 2019; 16: 1289-1296
- Determining cell type abundance and expression from bulk tissues with digital cytometry.Nat Biotechnol. 2019; 37: 773-782
- Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation.J Clin Invest. 2010; 120: 2699-2714
- RNA editing enzyme APOBEC3A promotes pro-inflammatory M1 macrophage polarization.Commun Biol. 2021; 4: 1-11
- Combined effects of pericytes in the tumor microenvironment.Stem Cell Int. 2015; 2015
- Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response.Proc Natl Acad Sci USA. 2021; 118
- NicheNet: modeling intercellular communication by linking ligands to target genes.Nat Methods. 2020; 17: 159-162
- Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma.J Clean Prod. 2020; 182
- IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade.J Clin Invest. 2017; 127: 2930-2940
- Mouse models of hepatocellular carcinoma: an overview and highlights for immunotherapy research.Nat Rev Gastroenterol Hepatol. 2018; 15: 536-554
- Hepatocellular carcinoma cells up-regulate PVRL1, stabilizing PVR and inhibiting the cytotoxic T-cell response via TIGIT to mediate tumor resistance to PD1 inhibitors in mice.Gastroenterology. 2020; 159: 609-623
- β-catenin activation promotes immune escape and resistance to anti–PD-1 therapy in hepatocellular carcinoma.Cancer Discov. 2019; 9: 1124-1141
- Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells.Cell Mol Immunol. 2021; 18: 112-127
- Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer.Cancer Cell. 2019; 36: 418-430.e6
- Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma.Cell. 2021; 184: 404-421.e16
- Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing.Cell. 2017; 169: 1342-1356.e16
- Diversity and biology of cancerassociated fibroblasts.Physiol Rev. 2021; 101: 147-176
- Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma.J Hepatol. 2022; 76: 862-873
- Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma.J Hepatol. 2020; 72: 307-319
- Safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the monoclonal antibody ASK8007 blocking osteopontin in patients with rheumatoid arthritis: a randomised, placebo controlled, proof-of-concept study.Ann Rheum Dis. 2012; 71: 180-185
- Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin α Vβ 3 engagement and PI3K/pAkt/NFκB signaling.Hepatology. 2012; 55: 594-608
- Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice.Gut. 2015; 64: 1120-1131
Published online: January 25, 2023
Accepted: January 16, 2023
Received in revised form: December 9, 2022
Received: March 22, 2022
© 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.