The P2X7 Receptor in Tumor Immunity
Fabio Grassi1, Benedetta De Ponte Conti1,2
1Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland.
Abstract:
Extracellular adenosine triphosphate (eATP) is a potent mediator of the immune response via stimulation of purinergic P2 receptors. ATP concentration in the extracellular space increases dramatically during tissue damage and eATP acts as a danger-associated molecular pattern (DAMP) to alert innate immune system cells for tissue repair. Similarly, eATP is present at hundreds of micromolar concentration in the tumor microenvironment (TME). However, its impact on antitumor immune response is still not well established, probably because of the complexity of the responses it induces in different cells constituting the TME. On one hand, ATP released by tumor cells concomitantly to cell death can contribute to immunogenic cell death (ICD) that is proinflammatory for the innate immune compartment and beneficial for tumor control, while on the other hand, eATP can foster immune-suppressive mechanisms within the TME, thus contributing to tumor progression and metastasis. It is well established that T-cell immunity is pivotal in limiting tumor growth and possibly eradicating neoplastic cells. T cells are limited though in their antitumor activity through different mechanisms, such as exhaustion, anergy, and senescence; the pathways resulting in these cellular outcomes are not clear. Here, we review the function of P2X7 receptor in conditioning T cell-dependent immunity against cancer.
Insights
Extracellular adenosine triphosphate (eATP) signals danger and initiates immune responses. This review explores how eATP and the P2X7 receptor influence T-cell immunity within the tumor microenvironment, impacting cancer progression.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Medicine
Background:
- Extracellular adenosine triphosphate (eATP) acts as a danger-associated molecular pattern (DAMP), activating innate immune cells via purinergic P2 receptors.
- Elevated eATP levels in the tumor microenvironment (TME) have complex, dual roles in antitumor immunity, potentially promoting both inflammation and immunosuppression.
- T-cell immunity is crucial for cancer control, but T cells can become dysfunctional through exhaustion, anergy, or senescence within the TME.
Purpose of the Study:
- To review the multifaceted role of extracellular adenosine triphosphate (eATP) in the tumor microenvironment (TME).
- To elucidate the function of the P2X7 receptor in modulating T-cell-dependent antitumor immunity.
- To clarify pathways leading to T-cell dysfunction (exhaustion, anergy, senescence) in cancer.
Main Methods:
- Literature review of studies investigating eATP, P2 receptors, and T-cell responses in cancer.
- Analysis of the dual role of eATP in promoting either anti-tumor inflammation or immune suppression.
- Examination of P2X7 receptor's involvement in T-cell exhaustion, anergy, and senescence.
Main Results:
- eATP can trigger both pro-inflammatory responses contributing to tumor control and immunosuppressive mechanisms fostering tumor progression.
- The P2X7 receptor plays a critical role in conditioning T-cell immunity against cancer, influencing T-cell function and survival.
- Understanding eATP's impact on T-cell dysfunction pathways is essential for developing effective cancer immunotherapies.
Conclusions:
- Extracellular adenosine triphosphate (eATP) presents a complex signaling network within the tumor microenvironment, with significant implications for T-cell-mediated cancer immunity.
- The P2X7 receptor emerges as a key regulator of T-cell responses in cancer, highlighting its potential as a therapeutic target.
- Further research into eATP signaling and P2X7 receptor function is necessary to harness its potential for improving cancer treatment strategies.
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