The Role of IL-18 in P2RX7-Mediated Antitumor Immunity

Hreich, Serena Janho dit; Hofman, Paul; Vouret‐Craviari, Valérie

doi:10.3390/ijms24119235

Cited by 13 publications

(6 citation statements)

References 167 publications

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“…Cisplatin is a first-line drug in the treatment of gastric cancer. Concomitantly, P2X7 expression and the derived cytokine IL-18 have been recognized as gastric cancer biomarkers (13,14). Thus, the results suggested that ATP administration may be involved in the modulatory activity of P2X7, which can reverse the GE delay induced by cisplatin.…”

Section: Discussionmentioning

confidence: 94%

Moderate physical exercise and ATP modulate the P2X7 receptor and improve cisplatin-induced gastric emptying delay in rats

Gomes,

Santos,

Pinheiro

et al. 2024

Braz J Med Biol Res

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Patients undergoing chemotherapy with cisplatin commonly present gastrointestinal effects such as constipation and gastric emptying (GE) delay. Both the purinergic system and physical exercise modulate the gastrointestinal (GI) tract. In the current study, we investigated the role of ATP, physical exercise, and P2X7 receptor blocking on GE delay induced by cisplatin in rats. Male rats were divided into the following groups: control (C), cisplatin (Cis), exercise (Ex), Brilliant Blue G (BBG), ATP, Cis+Ex, Cis+ATP, Cis+BBG, Cis+Ex+BBG, Cis+Ex+BBG+ATP, and Cis+ATP+BBG. GE delay was induced by treatment with 1 mg/kg cisplatin (1 time/week for 5 weeks, ip). The moderate physical exercise was swimming (1 h/day, 5 days/week for 5 weeks). At the end of the treatment or exercise and 30 min before the GE assessment, some groups received BBG (50 mg/kg, sc) or ATP (2 mg/kg, sc). Then, GE was assessed after a 10-min postprandial period. Chronic use of Cis decreased GE delay (Po0.05) compared to the control group. Both exercise and ATP prevented (Po0.05) GE delay compared to Cis. The pretreatment with BBG significantly inhibited (Po0.05) the effect of exercise and ATP. On the other hand, the association between exercise and ATP reversed (Po0.05) the effect of the BBG and prevented GE delay. Therefore, we suggest that both exercise and treatment with ATP activate P2X7 receptors and prevent GE delay induced by cisplatin in rats.

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Section: Discussionmentioning

confidence: 94%

Moderate physical exercise and ATP modulate the P2X7 receptor and improve cisplatin-induced gastric emptying delay in rats

Gomes,

Santos,

Pinheiro

et al. 2024

Braz J Med Biol Res

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“…In particular, the ICI responding sample size was too small to allow the Cox model to function, which could explain why we were unable to conclude the prognostic value of free IL-18. In addition, we measured the levels of IL-18-related compounds in the plasma of patients, which could significantly differ from those found in the immediate vicinity of tumors, where immune cells directly interact with tumor cells and can participate in either pro or antitumor responses, as we recently discussed in [ 7 ]. Finally, some of the patients included in our cohort were previously treated with chemo or radiotherapy (see Table 1 ), which could also impact the levels of both IL-18-producing immune cells and IL-18-related compounds.…”

Section: Discussionmentioning

confidence: 99%

“…The contribution of IL-18 to tumor progression is controversial. Preclinical studies have shown that IL-18 is required to inhibit tumor growth using either il18 −/− or il18r1 −/− mice, or even by administrating recombinant IL-18 [ 7 ]. In NSCLC patients, IL-18 has been shown to be expressed by tumor cells and to be active, as suggested by its positive correlation with IFN-γ production [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Plasmatic Inactive IL-18 Predicts a Worse Overall Survival for Advanced Non-Small-Cell Lung Cancer with Early Metabolic Progression after Immunotherapy Initiation

Janho dit Hreich,

Humbert,

Pacé-Loscos

et al. 2024

Cancers

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The aim of this study was to assess the potential value of circulating active and inactive IL-18 levels in distinguishing pseudo and true tumor progression among NSCLC patients receiving immune checkpoint inhibitor treatments (ICIs). Methods: This ancillary study includes 195 patients with metastatic non-small-cell lung cancer (NSCLC) treated with ICI in monotherapy, either pembrolizumab or nivolumab. Plasmatic levels of IL-18-related compounds, comprising the inhibitor IL-18 binding protein (IL-18BP), the inactive IL-18 (corresponding to IL-18/IL-18BP complex), and the active free IL-18, were assayed by ELISA. Objective tumoral response was analyzed by 18FDG PET-CT at baseline, 7 weeks, and 3 months post treatment induction, using PERCIST criteria. Results: Plasmatic IL-18BP and total IL-18 levels are increased at baseline in NSCLC patients compared with healthy controls, whereas IL-18/IL-18BP complexes are decreased, and free IL-18 levels remain unchanged. Neither of the IL-18-related compounds allowed to discriminate ICI responding to nonresponding patients. However, inactive IL-18 levels allowed to discriminate patients with a first tumor progression, assessed after 7 weeks of treatment, with worse overall survival. In addition, we showed that neutrophil concentration is also a predictive indicator of patients’ outcomes with OS (HR = 2.6, p = 0.0001) and PFS (HR = 2.2, p = 0.001). Conclusions: Plasmatic levels of inactive IL-18, combined with circulating neutrophil concentrations, can effectively distinguish ICI nonresponding patients with better overall survival (OS), potentially guiding rapid decisions for therapeutic intensification.

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“…Another feature of P2 R X7 is its ability to activate the NLRP3 inflammasome, an event linked to potassium efflux ( Di et al, 2018 ; Muñoz-Planillo et al, 2013 ), which requires both P2 R X7 and TWIK2 activation ( Di et al, 2018 ) and leads to the release of mature IL-1β and IL-18 ( Perregaux et al, 2000 ), through gasdermin D pores. Consequently, P2 R X7 has the ability to trigger an immune response ( Janho Dit Hreich et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Activation of the P2RX7/IL-18 pathway in immune cells attenuates lung fibrosis

Hreich

Juhel

Leroy

et al. 2024

eLife

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Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease associated with progressive and irreversible deterioration of respiratory functions that lacks curative therapies. Despite IPF being associated with a dysregulated immune response, current antifibrotics aim only at limiting fibroproliferation. We show here that the P2RX7/IL-18/IFNG axis is downregulated in IPF patients and that P2RX7 has immunoregulatory functions. Using our positive modulator of P2RX7, we show that activation of the P2RX7/IL-18 axis in immune cells limits lung fibrosis progression in a mouse model by favoring an anti-fibrotic immune environment, with notably an enhanced IL-18-dependent IFN-γ production by lung T cells leading to a decreased production of IL-17 and TGFβ. Overall, we show the ability of the immune system to limit lung fibrosis progression by targeting the immunomodulator P2RX7. Hence, treatment with a small activator of P2RX7 may represent a promising strategy for patients with lung fibrosis.

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The Role of IL-18 in P2RX7-Mediated Antitumor Immunity

Cited by 13 publications

References 167 publications

Moderate physical exercise and ATP modulate the P2X7 receptor and improve cisplatin-induced gastric emptying delay in rats

Moderate physical exercise and ATP modulate the P2X7 receptor and improve cisplatin-induced gastric emptying delay in rats

Plasmatic Inactive IL-18 Predicts a Worse Overall Survival for Advanced Non-Small-Cell Lung Cancer with Early Metabolic Progression after Immunotherapy Initiation

Activation of the P2RX7/IL-18 pathway in immune cells attenuates lung fibrosis

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