DataVXAdvanced SciencePaper
journal article·2024-09Open access

Identification of Hypoxia‐ALCAMhigh Macrophage‐ Exhausted T Cell Axis in Tumor Microenvironment Remodeling for Immunotherapy Resistance

Zhenzhen Xun, Huanran Zhou, Mingyi Shen, Yao Liu, Chengcao Sun, Yanhua Du, Zhou Jiang, Liuqing Yang, Qing Zhang, Chunru Lin, Qingsong Hu, Youqiong Ye, Leng Han

Advanced Science· Volume 11· Issue 33
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Source abstract

Abstract

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, ALCAMhigh 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 ALCAMhigh 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 ALCAMhigh macrophage‐exhausted T cell axis, providing a novel immunotherapeutic strategy to overcome hypoxia‐induced resistance in cancers.
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Research context

OpenAlex topics: Immune cells in cancer · Nanoplatforms for cancer theranostics · Cancer Immunotherapy and Biomarkers

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Center for Immune‐Related Diseases at Shanghai Institute of Immunology Department of Gastroenterology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 China

Shanghai Institute of Immunology State Key Laboratory of Systems Medicine for Cancer Department of Immunology and Microbiology Shanghai Jiao Tong University School of Medicine Shanghai 200025 China

Department of Endocrinology The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 China

Department of Hepatobiliary Surgery Centre for Leading Medicine and Advanced Technologies of IHM The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei 230001 China

Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Simmons Comprehensive Cancer Center Department of Pathology University of Texas Southwestern Medical Center Dallas TX 75390 USA

Brown Center for Immunotherapy School of Medicine Indiana University Indianapolis IN 46202 USA

Department of Biostatistics and Health Data Science School of Medicine Indiana University Indianapolis IN 46202 USA

Department of Biochemistry and Molecular Biology McGovern Medical School at The University of Texas Health Science Center at Houston Houston TX 77030 USA

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Natural Science Foundation of Anhui Province · China Postdoctoral Science Foundation

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