Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy

Ma, Shijun; Zhao, Yue; Lee, Wee Chyan; Ong, Li-Teng; Lee, Puay Leng; Jiang, Zemin; Oguz, Gokce; Niu, Zhitong; Liu, Min; Goh, Jian Yuan; Wang, Wenyu; Bustos, Matías A.; Ehmsen, Sidse; Ramasamy, Adaikalavan; Hoon, Dave S. B.; Ditzel, Henrik J.; Tan, Ern Yu; Chen, Qingfeng; Q, Yu

doi:10.1038/s41467-022-31764-9

Cited by 77 publications

(59 citation statements)

References 62 publications

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“…Hypoxic effects on immune cells also lead to insufficient PD‐L1 and PD‐L2 responses. 110 Targeting HIF‐1α with drugs or genes can inhibit PD‐L1 expression in the TME and enhance interferon production by T cells. 111 , 112 , 113 Targeting HIF‐1α reverses immune dysfunction and overcomes resistance to PD‐L1 blockade.…”

Section: The Role Of Hypoxia In Tumor Progressionmentioning

confidence: 99%

Hypoxia signaling in cancer: Implications for therapeutic interventions

Zhuang

Liu

et al. 2023

MedComm

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Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia‐targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.

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Section: The Role Of Hypoxia In Tumor Progressionmentioning

confidence: 99%

Hypoxia signaling in cancer: Implications for therapeutic interventions

Zhuang

Liu

et al. 2023

MedComm

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“…A study of exhausted CD8+ T cells in humans and a chronic viral infection mouse model by Sen et al revealed that a state-specific epigenetic landscape organized into functional modules of enhancers is required for exhaustion [ 124 ]. Using an in vitro system that models human T cell exhaustion, our data recently reported that hypoxia in the TME induces transcriptional suppression of the immune effectors IFN-γ, tumor necrosis factor α (TNFα), and granzyme B, resulting in immune effector cell dysfunction and resistance to immunotherapy [ 128 ]. Furthermore, the chromatin remodeling enforced by HIF1α interaction with HDAC1 and subsequent dependence on PRC is identified as a crucial epigenetic mechanism conferring immune effector suppression.…”

Section: Stromal Mechanisms Reshaping the Tme And Tumor Immune Responsementioning

confidence: 99%

Intimate communications within the tumor microenvironment: stromal factors function as an orchestra

Cheng

Wang

2023

J Biomed Sci

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Extensive studies of the tumor microenvironment (TME) in the last decade have reformed the view of cancer as a tumor cell-centric disease. The tumor microenvironment, especially termed the "seed and soil" theory, has emerged as the key determinant in cancer development and therapeutic resistance. The TME mainly consists of tumor cells, stromal cells such as fibroblasts, immune cells, and other noncellular components. Within the TME, intimate communications among these components largely determine the fate of the tumor. The pivotal roles of the stroma, especially cancer-associated fibroblasts (CAFs), the most common component within the TME, have been revealed in tumorigenesis, tumor progression, therapeutic response, and tumor immunity. A better understanding of the function of the TME sheds light on tumor therapy. In this review, we summarize the emerging understanding of stromal factors, especially CAFs, in cancer progression, drug resistance, and tumor immunity with an emphasis on their functions in epigenetic regulation. Moreover, the importance of epigenetic regulation in reshaping the TME and the basic biological principles underpinning the synergy between epigenetic therapy and immunotherapy will be further discussed.

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“…As an environmental stimulator, hypoxia has a conflicting effect on anti-tumor immunity. Effector T cells would undergo epigenetic reprogramming upon hypoxia exposure, and the altered epigenetic regulation reduces their transcription and function ( Ford et al, 2022 ; Ma et al, 2022 ). In contrast, another study demonstrated that hypoxia-inducible factor-1α (HIF-1α) deletion led to the reduction in T cell infiltration and tumor killing during hypoxia conditions ( Palazon et al, 2017 ).…”

Section: The Glucose Metabolism Features In Tumor Microenvironmentmentioning

confidence: 99%

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

Chu

Tian

Yang

et al. 2022

Front. Cell Dev. Biol.

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Cancer cells and immune cells all undergo remarkably metabolic reprogramming during the oncogenesis and tumor immunogenic killing processes. The increased dependency on glycolysis is the most typical trait, profoundly involved in the tumor immune microenvironment and cancer immunity regulation. However, how to best utilize glycolytic targets to boost anti-tumor immunity and improve immunotherapies are not fully illustrated. In this review, we describe the glycolytic remodeling of various immune cells within the tumor microenvironment (TME) and the deleterious effects of limited nutrients and acidification derived from enhanced tumor glycolysis on immunological anti-tumor capacity. Moreover, we elucidate the underlying regulatory mechanisms of glycolytic reprogramming, including the crosstalk between metabolic pathways and immune checkpoint signaling. Importantly, we summarize the potential glycolysis-related targets that are expected to improve immunotherapy benefits. Our understanding of metabolic effects on anti-tumor immunity will be instrumental for future therapeutic regimen development.

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Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy

Cited by 77 publications

References 62 publications

Hypoxia signaling in cancer: Implications for therapeutic interventions

Hypoxia signaling in cancer: Implications for therapeutic interventions

Intimate communications within the tumor microenvironment: stromal factors function as an orchestra

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

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