Faculty, Staff and Student Publications
Publication Date
9-1-2024
Journal
Advanced Science
Abstract
Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single‐cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia‐based intercellular communication hub consisting of malignant cells, ALCAM high macrophages, and exhausted CD8+ T cells around the tumor boundary. A hypoxic microenvironment promotes binding of HIF‐1α complex is demonstrated to the ALCAM promoter therefore increasing its expression in macrophages, and the ALCAM high macrophages co‐localize with exhausted CD8+ T cells in the tumor spatial microenvironment and promote T cell exhaustion. Preclinically, HIF‐1ɑ inhibition reduces ALCAM expression in macrophages and exhausted CD8+ T cells and potentiates T cell antitumor function to enhance immunotherapy efficacy. This study reveals the systematic landscape of hypoxia at single‐cell resolution and spatial architecture and highlights the effect of hypoxia on immunotherapy resistance through the ALCAM high macrophage‐exhausted T cell axis, providing a novel immunotherapeutic strategy to overcome hypoxia‐induced resistance in cancers.
Keywords
Tumor Microenvironment, Immunotherapy, Macrophages, Mice, Animals, Humans, CD8-Positive T-Lymphocytes, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia, Disease Models, Animal, Cell Line, Tumor, Neoplasms, ALCAM + macrophage, cancer immunotherapy, exhausted T cell, hypoxia, spatial transcriptomics
DOI
10.1002/advs.202309885
PMID
38956900
PMCID
PMC11434037
PubMedCentral® Posted Date
7-2-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons