CXCL12+ tumor-associated endothelial cells promote immune resistance in hepatocellular carcinoma

Abstract

Background & aims: The tumor microenvironment (TME) plays a crucial role in the limited efficacy of existing treatments for hepatocellular carcinoma (HCC), with tumor-associated endothelial cells (TECs) serving as fundamental TME components that substantially influence tumor progression and treatment efficacy. However, the precise roles and mechanisms of TECs in HCC remain inadequately understood.

Methods: We employed a multi-omics profiling strategy to investigate the single-cell and spatiotemporal evolution of TECs within the microenvironment of HCC tumors, showcasing varied responses to immunotherapy. Through an analysis of a clinical cohort of patients with HCC, we explored the correlation between TEC subpopulations and immunotherapy outcomes. The influence of TEC subsets on the immune microenvironment was confirmed through comprehensive in vitro and in vivo studies. To further explore the mechanisms of distinct TEC subpopulations in microenvironmental modulation and their impact on immunotherapy, we utilized TEC subset-specific knockout mouse models as well as humanized mouse models.

Results: In this study, we identified a new subset of CXCL12⁺ TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12⁺ TECs impede the differentiation of CD8⁺ naïve T cells into CD8⁺ cytotoxic T cells by secreting CXCL12. Furthermore, they attract myeloid-derived suppressor cells (MDSCs). A bispecific antibody was developed to target both CXCL12 and PD1 specifically, showing significant promise in bolstering anti-tumor immune responses and advancing HCC therapy.

Conclusions: CXCL12⁺ TECs are pivotal in mediating immunosuppression within the HCC microenvironment and targeting CXCL12⁺ TECs presents a promising approach to augment the efficacy of immunotherapies in patients with HCC.

Impact and implications: This investigation reveals a pivotal mechanism wherein CXCL12⁺ tumor-associated endothelial cells (TECs) emerge as crucial modulators of immune suppression in the tumor microenvironment of hepatocellular carcinoma (HCC). The discovery of CXCL12⁺ TECs as inhibitors of CD8⁺ naïve T cell activation and recruiters of myeloid-derived suppressor cells significantly advances our grasp of the dynamic between HCC and immune regulation. Moreover, the development and application of a bispecific antibody precisely targeting CXCL12 and PD1 has proven to enhance immune responses in a humanized mouse HCC model. This finding underscores a promising therapeutic direction for HCC, offering the potential to amplify the impact of current immunotherapies.

Keywords: CXCL12; Hepatocellular carcinoma; Immunosuppression; Immunotherapy; Tumor microenvironment; Tumor-associated endothelial cells.