Hypoxia‐driven immunosuppression by Treg and type‐2 conventional dendritic cells in HCC

Abstract

Background and Aims Hypoxia is one of the central players in shaping the immune context of the tumor microenvironment (TME). However, the complex interplay between immune cell infiltrates within the hypoxic TME of HCC remains to be elucidated. Approach and Results We analyzed the immune landscapes of hypoxia‐low and hypoxia‐high tumor regions using cytometry by time of light, immunohistochemistry, and transcriptomic analyses. The mechanisms of immunosuppression in immune subsets of interest were further explored using in vitro hypoxia assays. Regulatory T cells (Tregs) and a number of immunosuppressive myeloid subsets, including M2 macrophages and human leukocyte antigen–DR isotype (HLA‐DRlo) type 2 conventional dendritic cell (cDC2), were found to be significantly enriched in hypoxia‐high tumor regions. On the other hand, the abundance of active granzyme Bhi PD‐1lo CD8+ T cells in hypoxia‐low tumor regions implied a relatively active immune landscape compared with hypoxia‐high regions. The up‐regulation of cancer‐associated genes in the tumor tissues and immunosuppressive genes in the tumor‐infiltrating leukocytes supported a highly pro‐tumorigenic network in hypoxic HCC. Chemokine genes such as CCL20 (C‐C motif chemokine ligand 20) and CXCL5 (C‐X‐C motif chemokine ligand 5) were associated with recruitment of both Tregs and HLA‐DRlo cDC2 to hypoxia‐high microenvironments. The interaction between Tregs and cDC2 under a hypoxic TME resulted in a loss of antigen‐presenting HLA‐DR on cDC2. Conclusions We uncovered the unique immunosuppressive landscapes and identified key immune subsets enriched in hypoxic HCC. In particular, we identified a potential Treg‐mediated immunosuppression through interaction with a cDC2 subset in HCC that could be exploited for immunotherapies.

Hypoxia-Related Signature Is a Prognostic Biomarker of Pancreatic Cancer

“…Disease Markers conventional dendritic cells in hepatocellular carcinoma [10]. These results indicated that hypoxia played important roles in the regulation of immune cells in cancers.…”

“…For example, hypoxia was shown to be a dominant remodeler of the effector T cell surface proteome, relative to activation and regulatory T cell suppression [ 9 ]. Hypoxia was also found to drive immunosuppression by Treg and type-2 conventional dendritic cells in hepatocellular carcinoma [ 10 ]. These results indicated that hypoxia played important roles in the regulation of immune cells in cancers.…”

NK cells and solid tumors: therapeutic potential and persisting obstacles

“…Finally, hypoxic tumor regions are enriched in a variety of immunosuppressive cells that interfere with NK cell functions (see below), including (but not limited to): T REG cells [93][94][95], M2-like tumor-associated macrophages (TAMs) [96,97] and myeloid-derived suppressor cells (MDSCs) [98][99][100].…”

A potential pathogenic hypoxia-related gene HK2 in necrotizing enterocolitis (NEC) of newborns

“…LncRNA CYB561D2 has been indicated to activate STAT3 and lead to the immunosuppression in brain tumor [29]. Meanwhile, hypoxia was a crucial factor driving immunosuppression in various tumors [30]. However, whether CYB561D2 and HK2 could exert similar roles under hypoxia in NEC should be further investigated.…”