Highlights
- •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.
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.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: January 25, 2023
Accepted:
January 16,
2023
Received in revised form:
December 9,
2022
Received:
March 22,
2022
Identification
Copyright
© 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
