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Hypoxia‐driven immunosuppression by Treg and type‐2 conventional dendritic cells in HCC
Author(s) -
Suthen Sheena,
Lim Chun Jye,
Nguyen Phuong H. D.,
Dutertre CharlesAntoine,
Lai Hannah L. H.,
Wasser Martin,
Chua Camillus,
Lim Tony K. H.,
Leow Wei Qiang,
Loh Tracy Jiezhen,
Wan Wei Keat,
Pang Yin Huei,
Soon Gwyneth,
Cheow Peng Chung,
Kam Juinn Huar,
Iyer Shridhar,
Kow Alfred,
Tam Wai Leong,
Shuen Timothy W. H.,
Toh Han Chong,
Dan Yock Young,
Bonney Glenn K.,
Chan Chung Yip,
Chung Alexander,
Goh Brian K. P.,
Zhai Weiwei,
Ginhoux Florent,
Chow Pierce K. H.,
Albani Salvatore,
Chew Valerie
Publication year - 2022
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.32419
Subject(s) - immune system , biology , tumor microenvironment , chemokine , immunology , ccl20 , cd8 , cancer research , immunosuppression , cxcl10 , chemokine receptor
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‐DR lo ) 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 B hi PD‐1 lo 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‐DR lo 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.