# Unlocking IL-18: A hidden key in cancer immunity

Shima Sepehri-Manesh, Marion Debeaud, Valerie Vouret-Craviari

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Shima Sepehri-Manesh, Marion Debeaud, Valerie Vouret-Craviari. Unlocking IL-18: A hidden key in cancer immunity. Seminars in Immunology, 2025, 80, pp.101997. 10.1016/j.smim.2025.101997. hal-05323264

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Review

Unlocking IL-18: A hidden key in cancer immunity

Shima Sepehri-Manesh <sup>a,b</sup>, Marion Debeaud <sup>a,b</sup>, Valerie Vouret-Craviari <sup>a,b,*</sup>

ARTICLE INFO

Keywords:

Antitumor immunity
IFN-γ
Cancer progression

A B S T R A C T

The IL-1 family comprises 11 cytokines, including IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-18, IL-33, and IL-36 cytokines to IL-37 and IL-38, that modulate innate immune system activity. In addition to their role in innate immunity, IL-1 family members can activate and enhance the function of polarized T cells. For example, IL-33 primarily influences T helper 2 (T<sub>H</sub>2) cells, IL-1 plays a central role in the differentiation of T<sub>H</sub>17 cells, and IL-18 predominantly affects T<sub>H</sub>1 cells. The IL-1 family members participated in various biological functions as described elsewhere in this special issue. Here, we provide an overview on IL-18, originally called IFN-γ inducing factor, and its role in impacting cancer immunity.

1. IL-18 production

IL18 gene is somehow unique in the IL-1 family. Many of the encoding genes of the IL-1 family members are clustered in a short region of human chromosome 2, *IL18* is located on chromosome 11. Unlike other IL-1 family pro-inflammatory cytokines, which are typically induced only upon appropriate stimulation, *IL18* stands out for its constitutive expression: both mRNA and the inactive protein precursor are readily detectable in unstimulated human myeloid cell lines and PBMCs [1]. Koyama *et al*. later demonstrated the molecular basis of this distinct expression pattern, showing that a functional PU.1 binding site and a GC-rich promoter region are essential for the basal transcriptional activity of the human *IL18* gene [2]. *IL18* precursor is also constitutively expressed by endothelial cells, keratinocytes or intestinal epithelial cells throughout the gastrointestinal tract, a characteristic shared with *IL1A* and *IL33* [3,4]

The generation of biologically active IL-18 requires proteolytic cleavage of its inactive precursor, pro-IL-18, by caspase-1 followed by its release into the extracellular milieu via gasdermin D. Activation of caspase-1 occurs through a variety of canonical inflammasomes, which are typically assembled by NOD-like receptors (NLRs), AIM2-like receptors, or members of the TRIM protein family, all of which contain either a CARD or PYD domain to mediate inflammasome formation [5,6]

Among the various inflammasomes, the NLRP3 inflammasome is the most extensively studied. NLRP3 (NOD-like receptor family, pyrin domain containing 3) is a member of the NLR family-pattern recognition receptors (PRRs) that detect cellular stress or danger signals [7]. This

positions NLRP3 as a key sensor in the initiation of immune responses, particularly relevant in the context of inflammation-associated diseases, including cancer. The activation mechanism occurs in two distinct steps, priming and oligomerization/activation. During priming, stimuli such as Toll-like receptors (TLRs), TNF, or IL-1β trigger NF-κB signaling, leading to the transcription of NLRP3, pro-IL1β and pro-IL-18. The NLRP3 inflammasome consists of the adapter protein ASC, which contains a pyrin domain (PYD) that binds to the PYD of NLRP3, as well as a caspase activation and recruitment domain (CARD) that engages with the CARD of caspase-1. When the inflammasome is activated, oligomerized ASC recruits caspase-1, which becomes active through self-cleavage triggered by close molecular proximity. The activation of the complex is triggered by a wide variety of stimuli including crystalline and particulate matter (such as uric acid crystals, silica, asbestos and alum), pore-forming toxins, RNA-DNA hybrids, several viral, bacterial, fungal and protozoan pathogens and extracellular ATP [8]. All of these stimuli lead to a reduction in intracellular potassium levels, a key event sufficient to trigger NLRP3 activation. Among these triggers, the extracellular ATP (eATP)/P2RX7 axis is recognized as one of the most potent activators of the NLRP3 inflammasome. While potassium efflux is a common feature of all P2X receptors and several other potassium channels, they alone are insufficient to activate NLRP3. In contrast, P2RX7 possesses a unique C-terminal domain essential for NLRP3 activation via ATP. Deletion of this domain abolishes NLRP3 activation and IL-1β release [9]. Unlike other P2X receptors, P2RX7 does not undergo desensitization [10], allowing for sustained potassium efflux, which may enhance NLRP3 activation. Furthermore, NLRP3 and P2RX7 have

<footnote><sup>a</sup> Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France</footnote>

<footnote><sup>b</sup> IHU RespirERA, Nice, France</footnote>

<footnote>* Corresponding author at: Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France.
E-mail address: valerie.vouret@univ-cotedazur.fr (V. Vouret-Craviari).</footnote>
been shown to interact at the plasma membrane, either directly [11] or
indirectly via the scaffold protein Paxillin, promoting inflammasome
assembly. Importantly, the activation of NLRP3 via P2RX7 has been
shown to depend on the involvement of the potassium channel TWIK2.
The coordinated action of both receptors enhances potassium efflux,
contributing to the effective activation of the inflammasome [12]. In
addition to potassium efflux, P2RX7 also mediates calcium influx, which
has been implicated in NLRP3 assembly through mechanisms involving
reactive oxygen species (ROS) production and mitochondrial depolar-
zation [13]. Altogether, the robust capacity of P2RX7 to activate NLRP3
likely stems from its ability to drive both calcium influx and potassium
efflux, its interaction with NLRP3 and associated proteins, and its
resistance to desensitization, making it a central player in inflamma-
some activation. The role of the NLRP3 inflammasome in cancer pro-
gression and therapeutic response remains an active area of research but
lies beyond the scope of this review.

In addition, mature IL-18 can be processed by the non-canonical
inflammasome involving caspases-4/5 in humans. This mode of acti-
vation is particularly noteworthy because it is the only one described to
differentially regulate the production of mature IL-18 and IL-1β. While
caspase-4/5 cleaves IL-18 at D36 to generate the active cytokine, it
cleaves IL-1β at D27, producing a p27 IL-1β fragment that is unable to
activate downstream IL-1 receptor signaling [14]. Mature IL-18 can also
be processed through inflammasome-independent mechanisms,
including caspase-8 activation downstream of FasL binding to the Fas
death receptor, as well as by other proteases mainly produced by im-
mune cells, such as elastase, cathepsins, and granzyme B [15].

## 2. IL-18 signaling

IL-18 signaling closely resembles that of IL-1β. It initiates by binding to the IL-18 receptor alpha subunit (IL-18Rα or IL-18R1), which subsequently recruits the beta subunit (IL-18Rβ or IL-18RAP) to activate the MYD88/NF-κB signaling pathway. Notably, IL-18Rβ expression is restricted to specific immune cells, namely T cells, natural killer (NK) cells, and dendritic cells [16]. Therefore, only these immune cells have the ability to stimulate IFN-γ production through engagement of the IL-18Rα/IL-18Rβ receptor complex.

Interestingly, IL-18 has a higher binding affinity for its natural in-
hibitor, IL-18 Binding Protein (IL-18BP), than for its receptor. IL-18BP is
constitutively secreted in large amounts and functions as a decoy re-
ceptor, limiting IL-18 activity by preventing its interaction with cell
surface receptors. This inhibitory mechanism also operates as a feedback
loop, as IL-18BP expression is upregulated in response to elevated IFN-γ
levels [16]. Since each IL-18BP molecule binds to a single IL-18 mole-
cule, it is possible to determine the proportion of bound versus free IL-18
in a solution containing both [17]. This balance, and particularly the
concentration of free IL-18, may be more clinically relevant than total
IL-18 levels when interpreting patient data. For this purpose, a new
ELISA to assay free IL-18 was recently developed by a Swiss company.

## 3. The role of IL-18 in cancer progression

### 3.1. IL-18: an antitumoral cytokine

Preclinical studies modeling various types of cancer have demon-
strated that IL-18 is essential for suppressing tumor growth, as shown
using IL-18-deficient (Il18r-/-) or IL-18 receptor-deficient (Il18r1r-/-)
mice, as well as through the administration of recombinant IL-18 and
neutralizing anti-IL-18 antibodies.

Using the AOM/DSS-induced colon cancer model in *Nlrp3*-/- mice, it was demonstrated that reduced IL-18 levels led to impaired production and activation of the tumor suppressors IFN-γ and STAT1, respectively. These findings highlight the critical role of NLRP3 inflammasome-dependent IL-18 production in protecting against colorectal tumorigenesis [18,19]. In line with these findings, systemic

administration of IL-18 in both the AOM/DSS model and the MC38 subcutaneous tumor model reduced disease severity and enhanced the cytotoxic activity of NK cells, as well as CD4⁺ and CD8⁺ T cells, thereby demonstrating IL-18's capacity to strengthen antitumor immunity by promoting IFN-γ production [20–22]. Additionally, both endogenous and administered IL-18 have been reported to suppress the spread of MC38 colon cancer cells to the liver by promoting NK cell activation and boosting their FasL-dependent cytotoxic functions [23]. Similar results have been shown in pancreatic, metastatic and non-metastatic melanoma mouse models, where *in vivo* administration of IL-18 slowed tumor growth. From a mechanistic perspective, these studies underscore the close association between IL-18 and the activation and cytotoxic functions of CD4⁺ and CD8⁺ T cells, as well as NK cells [22,24,25]. They also highlight IL-18's role in promoting immune–tumor cell interactions and the strong induction of memory T cell responses [26]. In light with these findings, it was shown in a melanoma mouse model treated with radiation therapy that adoptive transfer of NK cells pre-activated *in vitro* with IL-18, IL-12 (a key inducer of IFN-γ), and IL-15 (an NK cell activator) enhanced antitumor immunity and reduced lung metastases. This therapeutic effect was associated with increased accumulation and cytotoxic activity of endogenous NK cells *in vivo* and was critically dependent on the presence of CD4⁺ T cells [27]. A similar enhancement of NK cell cytotoxicity was observed in human NK cells derived from both patients with metastatic melanoma [28] and healthy donors, leading to improved killing of three-dimensional spheroids from human colon, melanoma, glioblastoma, prostate, breast, and ovarian tumor cell lines [29].

Notably, the antitumor function of IL-18 has been recognized in cancer patients. In plasmas of non-small cell lung cancer patients, the levels of IL-18 and IFN-γ are lower compared to those of healthy subjects [30,31]. This tendency has been confirmed in tumor tissue of colon cancer, melanoma, thyroid and esophageal cancer patients. Further, low levels of IL-18 correlated with the presence of metastases, a poor outcome [32–36] and increased risk of developing acute myeloid leukemia [37]. Additionally, elevated IL-18 levels correlate with increased CD8⁺ T cell and NK cell infiltration and activity in melanoma [38], colorectal cancer [39] and thyroid carcinoma [35]. Similarly, CD8⁺ T cells in non-small cell lung cancer express high levels of IL-18R and exhibit IL-18-dependent cytotoxicity [30]. IL-18R expression in lung squamous carcinoma is also associated with enhanced immune infiltration and improved survival [40]. However, and as discussed above, the levels of IL-18 are not always correlated with IFN-γ-induced antitumor activity since most of the circulating IL-18 is in a tight complex with its antagonist, the IL-18BP. For instance, IL-18BP levels have been shown to be high in sera of patients with ovarian [41], non-small cell lung cancer [31] and prostate cancer [40]. In sera and tissue of ovarian cancer patients, IL-18 levels are high but inactive as evidence by the lack of IFN-γ production [42]. This supports the notion that the loss of IL-18 biological activity may contribute to tumor immune escape and suggests that free IL-18 levels could serve as a novel checkpoint biomarker in cancer.

### 3.2. IL-18: a pro-tumoral cytokine

Despite substantial evidence supporting the beneficial role of IL-18 in promoting tumor cytotoxicity, elevated IL-18 levels have also been associated with tumor progression. Melanoma cells express bioactive IL-18, which enhances ROS-dependent FasL expression and suppresses the immune system. Blocking IL-18 using either an anti-IL-18 antibody or IL-18 siRNA reactivates the susceptibility of natural killer to tumor cells both *in vitro* and *in vivo*, highlighting the role of IL-18 as a survival factor for melanoma cells [43]. IL-18 has also a direct pro-tumoral activity which depends on NLRP3 activation and its signaling through the IL-18R to induce a CD8⁺T-cell exhaustion in a murine pancreatic cancer model [44]. This finding was confirmed in patients with pancreatic carcinoma, where TCGA analysis revealed an association between NLRP3-mediated
IL-18 signaling and shorter survival, suggesting that the NLRP3/IL-18 axis may be a potential target for immunotherapy. High IL-18 levels also affect NK cell functions, a response that depends on the IL-18 dependent up regulation of PD-1 on NK cells to mediate a pro-metastatic effect [45]. IL-18 has been shown to increase melanoma migration and invasion by regulating vascular cell adhesion molecule-1 [46]. Further, an amplification loop involving VEGF, activation of the ERK1/2 pathway, IL-18 production and migration has been shown to play important role in the pathogenesis of gastric cancer [47]. In this particular area, at least two question remains open: Does IL-18 act directly on tumor cells, which are not typically known to express IL-18 receptors? If not, which immune cells mediate the effects of IL-18, leading to the production of growth factors?

### 3.3. IL-18, its partners and their role in tumor trajectory

As depicted above, IL-18 can be either beneficial or detrimental to tumor progression, depending on the microenvironment in which it is present. Indeed, IL-18 can act as a Th1 or Th2 immune response inducer, this directly depends on the expression levels of IL-18Rα and IL-18Rβ and the accompanying cytokines. Importantly, expression of the trans-ducing subunit IL-18Rβ is observed in hematopoietic cells implying that those cells are required to mediate IL-18 reactions caused by IL-18 [48]. Notably, in the absence of IL-12 or IL-15 in the microenvironment, IL-18 does not induce IFN-γ production, as these cytokines upregulate the expression of IL-18Rβ, which is essential for IL-18 signal transduction. These findings collectively suggest that the anti-tumor activity of IL-18 depends on a complex tumor microenvironment, including the presence of immune cells expressing IL-18 receptors and co-stimulatory cytokines such as IL-12. Conversely, when IL-2 is present instead of IL-12, IL-18 promotes a Th2-type immune response, leading to the survival of regulatory T cells and the enhancement of their immunosuppressive functions, thereby impairing antitumor immunity [49]. Another layer of complexity involves the expression of IL-18BP, which acts as a decoy receptor by limiting IL-18 activity through inhibition of its interaction with cell surface receptors. This regulatory mechanism is upregulated in response to increased levels of IFN-γ, thereby contributing to the modulation of IL-18 activity [16]. Therefore, investigating the role of IL-18 in cancer extends beyond merely measuring its presence, particularly given that most studies rely on quantification of IL-18 mRNA expression or the use of ELISA assays that detect total IL-18, that is, both the free, biologically active form and the fraction bound to IL-18BP. This can partly explain the discrepancies highlighted earlier. In addition, both the dosage and the source of IL-18 production are important in regulating the immunosuppressive function of this cytokine [45].

Given the concurrent presence of IL-18, its receptor (IL-18R), and the inhibitory binding protein IL-18BP within the tumor microenvironment (TME), enhancing the antitumor activity of IL-18 will require strategies that increase the levels of bioactive IL-18 independently of IL-18BP neutralization. Whereas the recombinant human IL-18 is well tolerated by patients [50], a phase II clinical trial in patients with metastatic melanoma to whom rIL-18 was given as monotherapy was abruptly stopped due to limited clinical efficacy [51]. Today combination approaches are investigated. For instance, one clinical trial (NCT01768338) tested the effect of recombinant IL-18, combined to anti CD20 antibody, to treat lymphoma. The results of this trial are still unknown. Along the same lines, a Phase 1 trial investigated the autologous stimulation of monocytes with IFN-α2b and IFN-γ for intraperitoneal administration in patients with recurrent ovarian cancer [52]. This approach, designed to induce a strong pro-inflammatory environment at the tumor site to eliminate cancer cells, demonstrated antitumor activity and acceptable tolerability [53]. Other researchers tested a fourth-generation anti-CD19 CAR T engineered to secrete IL-18 (huCART19-IL-18) in a clinical trial (NCT04684563) in patients with CD19-positive non-Hodgkin lymphoma or chronic lymphocytic

leukemia who had relapsed after two lines of treatment. This approach showed very promising efficacy with no unexpected side effect and a complete response in 52 % of the 21 patients tested [54].

Overall, these results support local administration, in close proximity to diseased cells, rather than systemic delivery. The key challenge moving forward will be to develop organ-specific modes of administration.

### 4. Strategies to increase IL-18 levels and/or efficacy

Since the pro-tumoral role of IL-18 appears to be associated with T cell and NK cell exhaustion, immune checkpoint inhibitors were employed to restore immune cell function and counteract the tumor-promoting effects of IL-18. For instance, it was shown that after the first round of αPD-L1 immunotherapy, IL-18 levels increase in sera of patients with multiple myeloma, non-small cell lung cancer, renal cell carcinoma and melanoma, which is linked to a reactivation and cytotoxicity of antitumor effector cells producing IFN-γ. To overcome the induction of IL-18 and its natural inhibitor IL-18BP, a decoy-resistant cytokine (DR-18) was engineered and demonstrated impressive antitumor efficacy in transplanted syngeneic mouse models [21]. The human version of DR-18 is currently being evaluated as a monotherapy and in combination with anti-PD-1 antibodies in a clinical trial for advanced solid malignancies (NCT04757042). Building on this approach, researchers further conjugated IL-18 to an anti-PD-1 antibody to develop an immunocytokine, BTP567, which is resistant to IL-18BP and selectively targets infiltrating PD-1⁺ CD8⁺ T cells to enhance their cytotoxic activity [55]. Alternatively, an mRNA-based approach was explored using synthetic mRNA encoding DR-18 in combination with mRNA encoding IL-12, with the goal of transiently expressing these cytokines directly at the tumor site. This proof-of-concept of a combination of mRNAs encoding cytokines for the local immunotherapy of cancer give very promising results and highlight once more the importance for a local versus systemic delivery of treatment [56].

In recent years, an alternative mechanism relying on the eATP/ P2X7/NLRP3 axis was explored to increase IL-18 levels. Beside its function in the bioenergetic metabolism of all cells, extracellular ATP (eATP), which is present at high levels in the tumor microenvironment [57], operates as a potent signal transducer by activating the purinergic receptors. In particular, the purinoreceptor P2X7 (P2RX7), expressed in tumors of different origin, is the most potent inducer of the NLRP3 inflammasome as discussed earlier [58]. Blocking the activity of ectonucleotidases involved in ATP degradation, specifically CD73 (NT5E) and CD39 (ENTPD1), using neutralizing antibodies has been shown to enhance antitumor immune responses via the P2RX7/NLRP3 signaling cascade. This approach led to reduced tumor progression in murine models of melanoma, fibrosarcoma, colon, and prostate cancers [59,60]. Along similar lines, our research group demonstrated that pharmacological activation of P2RX7 with a positive allosteric modulator, HEI3090, significantly inhibited tumor growth in mouse models of lung cancer and melanoma. This antitumor effect is mediated by dendritic cell-derived IL-18, which enhances immune responses, particularly IFN-γ production by CD4⁺ T cells and NK cells [61]. Notably, IL-18 has been shown to potentiate the effects of αPD-1 immune checkpoint inhibitors and chemotherapeutic agents, leading to more robust tumor regression. Activation of the P2RX7/IL-18 pathway using HEI3090 rendered lung and melanoma tumors more responsive to immunotherapy, resulting in an 80 % cure rate and providing protection against tumor rechallenge, thereby underscoring IL-18's role in promoting durable memory T cell responses [61]. Supporting this, IL-18 release by dendritic cells and engagement of the IL-18R/MyD88/IFN-γ axis during T cell activation has been linked to the expansion of memory T cell populations. Interestingly, IL-18 can also stimulate IFN-γ secretion independently of TCR activation. Together, these findings highlight the central role of IL-18 in enhancing cytotoxic T cell activity and memory formation in the context of antitumor immunity.
## 5. IL-18, a suitable biomarker for patient selection?

Considering IL-18's strong capacity to activate immune effector cells and enhance their cytotoxic functions, as well as its ability to improve responses to immunotherapy, recent research has explored its potential as a predictive biomarker for patient outcomes but also to evaluate whether patients may benefit from an immunotherapy. This is particularly relevant in light of the current lack of reliable markers to forecast immunotherapy efficacy. Whereas many studies investigate the potential of IL-18 as a biomarker for immunotherapy, as discussed by Janhodit-Hreich et al. [31,62], no report focusses on the level of active free IL-18, i.e., unbound to its inhibitor IL-18BP. Indeed, IL-18BP is present physiologically at high levels and has been shown to be further increased in several cancers, inhibiting even more IL-18 signaling. Of note, analyzing IL18 mRNA, is neither pertinent as it is expressed constitutively and requires a proteolytic cleavage before being synthesized and released as active cytokine. Building on the work of Migliorini and colleagues [17], our group conducted an ancillary study involving 195 patients with NSCLC to assess plasma levels of free active IL-18, IL-18BP, and the inactive IL-18/IL-18BP complex before and after immunotherapy. Our aim was to evaluate the predictive value of these IL-18-related compounds as compared to the neutrophil-to-lymphocytes ratio, a recognized biomarker for ICI response [63], just after the first round of treatment. We showed that plasmatic levels of inactive IL-18, combined with circulating neutrophil concentrations, can effectively distinguish ICI nonresponding patients with better overall survival, potentially guiding rapid decisions for therapeutic intensification. In this study, we also showed that the level of extrapolated free IL-18 tends to discriminate between true tumor progression versus pseudo progression. This result needs to be validated in a larger cohort. If confirmed, it would be highly significant, as a simple blood function could be sufficient to distinguish between pseudo-progressors, who should continue treatment, and true progressors, who need to stop it [31].

## 6. Conclusion

The exact role of IL-18 in cancer progression warrants further investigation to determine whether all cancer types would benefit from IL-18-mediated enhancement of immune-tumor cell interactions. Nevertheless, IL-18 emerges as a promising cytokine in cancer therapy due to its ability to stimulate antitumor immune responses, particularly by activating NK cells and cytotoxic T lymphocytes. Preclinical studies have demonstrated significant antitumor effects, and early-phase clinical trials have confirmed that recombinant IL-18 is well tolerated, although its clinical efficacy as a monotherapy remains limited, when administrated in a systemic way. However, the therapeutic potential of IL-18 appears to be hindered by negative regulatory mechanisms, notably the presence of IL-18BP, which neutralizes its activity. Novel strategies combining the local administration of recombinant IL-18 variants resistant to IL-18BP, in association with conventional immunotherapies, may overcome tumor resistance. These future strategies will benefit from the development of new biomaterials capable of delivering the cytokine in a timely and localized manner at the tumor site, or even within the tumor itself, as well as from the dual specificity strategy which could combine ICI with stable IL-18, enabling a synergistic action of two complementary therapeutic mechanisms to effectively unlock IL-18 and enhance its potent role in cancer immunity

### CRediT authorship contribution statement

**Marion Debeaud:** Validation. **Shima Sepehri-Manesh:** Writing – original draft. **VOURET-CRAVIARI valerie:** Funding acquisition, Writing – original draft, Writing – review & editing.

### Declaration of Competing Interest

The authors declare no conflict of interest.

### Acknowledgments

This paper is based upon work from COST Action CA21130, Supported by COST (European Cooperation in Science and Technology). This work was supported by ARC pour la recherche within the TRANSCAN-3 ERA-NET: Sustained collaboration of national and regional programmes in cancer research – Pur-Ther – ERP-2021-23682413 and the French National Research Agency, France 2030 action (ANR-23-IAHU-007).

### Author contribution

MB, SS-M and VV-C drafted the article and revised it critically for the scientific content.

### Data availability

No data was used for the research described in the article.

### References

[1] A.J. Puren, G. Fantuzzi, C.A. Dinarello, Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells, Proc. Natl. Acad. Sci. USA 96 (1999) 2256-2261, https://doi.org/10.1073/pnas.96.5.2256.

[2] N. Koyama, D. Hoelzer, O.G. Ottmann, Regulation of human IL-18 gene expression: interaction of PU.1 with GC-box binding protein is involved in human IL-18 expression in myeloid cells, Eur. J. Immunol. 34 (2004) 817-826, https://doi.org/10.1002/eji.200324420.

[3] C.A. Dinarello, IL-18: a TH1-inducing, proinflammatory cytokine and new member of the IL-1 family, J. Allergy Clin. Immunol. 103 (1999) 11-24, https://doi.org/10.1016/S0091-6749(99)70518-X.

[4] K. Kohno, M. Kurimoto, Interleukin 18, a cytokine which resembles IL-1 structurally and IL-12 functionally but exerts its effect independently of both, Clin. Immunol. Immunopathol. 86 (1998) 11-15, https://doi.org/10.1006/clin.1997.4475.

[5] Y. Gu, K. Kuida, H. Tsutsui, G. Ku, K. Hsiao, M.A. Fleming, N. Hayashi, K. Higashino, H. Okamura, K. Nakanishi, M. Kurimoto, T. Tanimoto, R.A. Flavell, V. Sato, M.W. Harding, D.J. Livingston, M.S.-S. Su, Activation of interferon-γ inducing factor mediated by interleukin-1β converting enzyme, Science 275 (1979) 206-209, https://doi.org/10.1126/science.275.5297.206.

[6] G. Kaplanski, Interleukin-18: biological properties and role in disease pathogenesis, Immunol. Rev. 281 (2018) 138-153, https://doi.org/10.1111/imr.12616.

[7] J.P.-Y. Ting, R.C. Levering, E.S. Alnemri, J. Bertin, J.M. Boss, B.K. Davis, R. A. Flavell, S.E. Girardin, A. Godzik, J.A. Harton, H.M. Hoffman, J.-P. Hugot, N. Inohara, A. MacKenzie, L.J. Maltais, G. Nunez, Y. Ogura, L.A. Otten, D. Philpott, J.C. Reed, W. Reith, S. Schreiber, V. Steimle, P.A. Ward, The NLR gene family: a standard nomenclature, Immunity 28 (2008) 285-287, https://doi.org/10.1016/j.immuni.2008.02.005.

[8] P. Broz, V.M. Dixit, Inflammasomes: mechanism of assembly, regulation and signalling, Nat. Rev. Immunol. 16 (2016) 407-420, https://doi.org/10.1038/nri.2016.58.

[9] M. Solle, J. Labasi, D.G. Perregaux, E. Stam, N. Petrushova, B.H. Koller, R. J. Griffiths, C.A. Gabel, Altered cytokine production in mice lacking P2X7Receptors, J. Biol. Chem. 276 (2001) 125-132, https://doi.org/10.1074/jbc.M006781200.

[10] P. Illes, C.E. Müller, K.A. Jacobson, T. Grutter, A. Nicke, S.J. Fountain, C. Kennedy, G. Schmalzing, M.F. Jarvis, S.S. Stojilkovic, B.F. King, F. Di Virgilio, Update of P2X receptor properties and their pharmacology: IUPHAR review 30, Br. J. Pharmacol. 178 (2021) 489-514, https://doi.org/10.1111/bph.15299.

[11] A. Franceschini, M. Capece, P. Chiozzi, S. Falzoni, J.M. Sanz, A.C. Sarti, M. Bonora, P. Pinton, F. Di Virgilio, The P2X7 receptor directly interacts with the NLRP3 inflammasome scaffold protein, FASEB J. 29 (2015) 2450-2461, https://doi.org/10.1096/fj.14-268714.

[12] A. Di, S. Xiong, Z. Ye, R.K.S. Malireddi, S. Kometani, M. Zhong, M. Mittal, Z. Hong, T.-D. Kanneganti, J. Rehman, A.B. Malik, The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation, Immunity 49 (2018) 56-65.e4, https://doi.org/10.1016/j.immuni.2018.04.032.

[13] G.-S. Lee, N. Subramanian, A.I. Kim, I. Aksentijevich, R. Goldbach-Mansky, D. B. Sacks, R.N. Germain, D.L. Kastner, J.J. Chae, The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP, Nature 492 (2012) 123-127, https://doi.org/10.1038/nature11588.

[14] P.M. Exconde, C. Hernandez-Chavez, C.M. Bourne, R.M. Richards, M.B. Bray, J. L. Lopez, T. Srivastava, M.S. Egan, J. Zhang, W. Yoo, S. Shin, B.M. Discher, C.
Y. Taabazuing, The tetrapeptide sequence of IL-18 and IL-1β regulates their recruitment and activation by inflammatory caspases, Cell Rep. 42 (2023) 113581, https://doi.org/10.1016/j.celrep.2023.113581.

[15] K. Yasuda, K. Nakanishi, H. Tsutsui, Interleukin-18 in health and disease, Int. J. Mol. Sci. 20 (2019) 649, https://doi.org/10.3390/ijms20030649.

[16] C.A. Dinarello, D. Novick, S. Kim, G. Kaplanski, Interleukin-18 and IL-18 binding protein, Front. Immunol. 4 (2013), https://doi.org/10.3389/fimmu.2013.00289.

[17] P. Migliorini, C. Anzilotti, F. Pratesi, P. Quattroni, M. Bargagna, C.A. Dinarello, D. Boraschi, Serum and urinary levels of IL-18 and its inhibitor IL-18BP in systemic lupus erythematosus, Eur. Cytokine Netw. 18 (2010) 264–271, https://doi.org/10.1684/ecn.2010.0210.

[18] Md.H. Zaki, K.L. Boyd, P. Vogel, M.B. Kastan, M. Lamkanfi, T.-D. Kanneganti, The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis, Immunity 32 (2010) 379–391, https://doi.org/10.1016/j.immuni.2010.03.003.

[19] R. Salcedo, A. Worschech, M. Cardone, Y. Jones, Z. Gyulai, R.-M. Dai, E. Wang, W. Ma, D. Haines, C. O'uGuin, F.M. Marincola, G. Trinchieri, MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18, J. Exp. Med. 207 (2010) 1625–1636, https://doi.org/10.1084/jem.20100199.

[20] D. Sharma, A. Malik, C.S. Guy, R. Karki, P. Vogel, T.-D. Kanneganti, Pyrin inflammasome regulates tight junction integrity to restrict colitis and tumorigenesis, Gastroenterology 154 (2018) 948–964.e8, https://doi.org/10.1053/j.gastro.2017.11.276.

[21] T. Zhou, W. Damsky, O.-E. Weizman, M.K. McGeary, K.P. Hartmann, C.E. Rosen, S. Fischer, R. Jackson, R.A. Flavell, J. Wang, M.F. Sanmamed, M.W. Bosenberg, A. M. Ring, IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy, Nature 583 (2020) 609–614, https://doi.org/10.1038/s41586-020-2422-6.

[22] J. Dupaul-Chicoine, A. Arabzadeh, M. Dagenais, T. Douglas, C. Champagne, A. Morizot, I.G. Rodrigue-Gervais, V. Breton, S.L. Colpitts, N. Beauchemin, M. Saleh, The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumorigenic activity, Immunity 43 (2015) 751–763, https://doi.org/10.1016/j.immuni.2015.08.013.

[23] T. Osaki, J.-M. Péron, Q. Cai, H. Okamura, P.D. Robbins, M. Kurimoto, M.T. Lotze, H. Tahara, IFN-γ-Inducing Factor/IL-18 administration mediates IFN-γ- and IL-12-Independent antitumor effects, J. Immunol. 160 (1998) 1742–1749, https://doi.org/10.4049/jimmunol.160.4.1742.

[24] C. Savid-Frontera, M.E. Viano, N.S. Baez, N.L. Lidon, Q. Fontaine, H.A. Young, L. Vimeux, E. Donnadieu, M.C. Rodriguez-Galan, Exploring the immunomodulatory role of virtual memory CD8+ t cells: role of IFN gamma in tumor growth control, Front. Immunol. 13 (2022), https://doi.org/10.3389/fimmu.2022.971001.

[25] I.-K. Choi, J.-S. Lee, S.-N. Zhang, J. Park, K.-M. Lee, C.H. Son, C.-O. Yun, Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of t cells expressing IL-12Rβ2 or IL-18Rα, Gene Ther. 18 (2011) 898–909, https://doi.org/10.1038/gt.2011.37.

[26] S.A. Minnie, O.G. Waltner, K.S. Ensbey, N.S. Nemychenkov, C.R. Schmidt, S. Bhise, S.R.W. Legg, G. Campoy, L.D. Samson, R.D. Kuns, T. Zhou, J.D. Huck, S. Vuckovic, D. Zamora, A. Yeh, A. Spencer, M. Koyama, K.A. Markey, S.W. Lane, M. Boeckh, A.M. Ring, S.N. Furlan, G.R. Hill, Depletion of exhausted alloreactive t cells enables targeting of stem-like memory t cells to generate tumor-specific immunity, Sci. Immunol. 7 (2022), https://doi.org/10.1126/sciimmun.alo3420.

[27] J. Ni, M. Miller, A. Stojanovic, N. Garbi, A. Cerenkova, S. Sustained effector function of IL-12/15/18–preactivated NK cells against established tumors, J. Exp. Med. 209 (2012) 2351–2365, https://doi.org/10.1084/jem.20120944.

[28] K. Mirjacić Martinović, N. Babović, R. Džodić, V. Jurisić, S. Matković, G. Konjević, Favorable in vitro effects of combined IL-12 and IL-18 treatment on NK cell cytotoxicity and CD25 receptor expression in metastatic melanoma patients, J. Transl. Med. 13 (2015) 120, https://doi.org/10.1186/s12967-015-0479-z.

[29] M. Aarsund, F.M. Segers, Y. Wu, M. Innjegdering, Comparison of characteristics and tumor targeting properties of extracellular vesicles derived from primary NK cells or NK-cell lines stimulated with IL-15 or IL-12/15/18, Cancer Immunol. Immunother. 71 (2022) 2227–2238, https://doi.org/10.1007/s00262-022-03161-0.

[30] E. Timperi, C. Focaccetti, D. Gallerano, M. Panetta, S. Spada, E. Gallo, P. Visca, F. Venuta, D. Diso, A. Prelaj, F. Longo, F. Facciolo, P. Nisticò, V. Barnaba, IL-18 receptor marks functional CD8+ t cells in non-small cell lung cancer, Oncoimmunology 6 (2017) e1328337, https://doi.org/10.1080/2162402X.2017.1328337.

[31] S. Janho dit Hreich, O. Humbert, T. Pacé-Looscos, R. Schiappa, T. Juhel, M. Ilié, V. Ferrari, J. Benzaquen, P. Hofman, V. Vouret-Craviari, Plasmatic inactive IL-18 predicts a worse overall survival for advanced non-small-cell lung cancer with early metabolic progression after immunotherapy initiation, Cancers 16 (2024) 2226, https://doi.org/10.3390/cancers16122226.

[32] F. Pagès, A. Berger, B. Henglein, B. Piqueras, C. Danel, F. Zinzindohoue, N. Thiounn, P.H. Cugnenc, W.H. Fridman, Modulation of interleukin-18 expression in human colon carcinoma: consequences for tumor immune surveillance, Int. J. Cancer 84 (1999) 326–330, https://doi.org/10.1002/(SICI)1097-0215(19990621)84:3<326::AID-LJC22>3.0.CO;2-K.

[33] X. Feng, Z. Zhang, P. Sun, G. Song, L. Wang, Z. Sun, N. Yuan, Q. Wang, L. Lun, Interleukin-18 is a prognostic marker and plays a tumor suppressive role in colon cancer, Dis. Markers 2020 (2020) 1–9, https://doi.org/10.1155/2020/6439614.

[34] M. Gil, K.E. Kim, Interleukin-18 is a prognostic biomarker correlated with CD8+ t cell and natural killer cell infiltration in skin cutaneous melanoma, J. Clin. Med. 8 (2019) 1993, https://doi.org/10.3390/jcm8111993.

[35] K. Jiang, B. Lin, Y. Zhang, K. Lu, F. Wu, D. Luo, A novel pyroptosis-related gene signature for prediction of disease-free survival in papillary thyroid carcinoma, J. Pers. Med 13 (2022) 85, https://doi.org/10.3390/jpm13010085.

[36] W. Xiao, P. Tang, Z. Sui, Y. Han, G. Zhao, X. Wu, Y. Yang, N. Zhu, L. Gong, Z. Yu, H. Zhang, Establishment of a risk model by integrating hypoxia genes in predicting prognosis of esophageal squamous cell carcinoma, Cancer Med. 12 (2023) 2117–2133, https://doi.org/10.1002/cam.45002.

[37] J. Song, A. Li, Y. Qian, B. Liu, L. Lv, D. Ye, X. Sun, Y. Mao, Genetically predicted circulating levels of cytokines and the risk of cancer, Front. Immunol. 13 (2022), https://doi.org/10.3389/fimmu.2022.886144.

[38] M. Gil, K.E. Kim, Interleukin-18 is a prognostic biomarker correlated with CD8+ t cell and natural killer cell infiltration in skin cutaneous melanoma, J. Clin. Med. 8 (2019) 1993, https://doi.org/10.3390/jcm8111993.

[39] L.B. Mutala, C. Deleine, M. Karakachoff, D. Dansette, K. Ducoin, R. Oger, O. Rousseau, J. Podevin, E. Duchalais, P. Fourquier, W.E.A. Thomas, P.-A. Gourraud, J. Bennouna, C. Brochier, N. Gervois, C. Bossard, A. Jarry, The Caspase-1/IL-18 axis of the inflammasome in tumor cells: a modulator of the Th1/Tc1 response of Tumor-Infiltrating t lymphocytes in colorectal cancer, Cancers 13 (2021) 189, https://doi.org/10.3390/cancers13020189.

[40] Q. Guo, C.-Y. Wu, N. Jiang, S. Tong, J.-H. Wan, X.-Y. Xiao, P.-Y. Mei, H.-S. Liu, S.-H. Wang, Downregulation of T-cell cytotoxic marker IL18R1 promotes cancer proliferation and migration and is associated with dismal prognosis and immunity in lung squamous cell carcinoma, Front. Immunol. 13 (2022), https://doi.org/10.3389/fimmu.2022.986447.

[41] G. Carbotti, G. Barisione, A.M. Orengo, A. Brizzolara, I. Airoldi, M. Bagnoli, P. Pinciroli, D. Mezzanzanica, M.G. Centurioni, M. Fabbi, S. Ferrini, The IL-18 antagonist IL-18-Binding protein is produced in the human ovarian cancer microenvironment, Clin. Cancer Res. 19 (2013) 4611–4620, https://doi.org/10.1158/1078-0432.CCR-13-0568.

[42] A.M. Orengo, M. Fabbi, L. Miglietta, C. Andreani, M. Bruzzone, A. Puppo, P. Cristoforoni, M.G. Centurioni, M. Gualco, S. Salvi, S. Boccardo, M. Truini, T. Piazza, S. Canevari, D. Mezzanzanica, S. Ferrini, Interleukin (IL)-18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor, Int. J. Cancer 129 (2011) 1116–1125, https://doi.org/10.1002/ijc.25757.

[43] D. Cho, H. Song, Y.M. Kim, D. Houh, D.Y. Hur, H. Park, D. Yoon, K.H. Pyun, W. J. Lee, M. Kurimoto, Y.B. Kim, Y.S. Kim, I. Choi, Endogenous Interleukin-18 modulates immune escape of murine melanoma cells by regulating the expression of fas ligand and reactive oxygen intermediates, Cancer Res. 60 (2000) 2703–2709.

[44] V. Lutz, V.M. Hellmund, F.S.R. Picard, H. Raifer, T. Ruckenbrod, M. Klein, T. Bopp, R. Savai, P. Duewell, C.U. Keber, A. Weigert, H.-R. Chung, M. Buchholz, A. Menke, T.M. Gress, M. Huber, C. Bauer, IL18 receptor signaling regulates Tumor-Reactive CD8+ T-cell exhaustion via activation of the IL2/STAT5/mTOR pathway in a pancreatic cancer model, Cancer Immunol. Res. 11 (2023) 421–434, https://doi.org/10.1158/2326-6066.CIR-22-0398.

[45] M. Terme, E. Ullrich, L. Aymeric, K. Meinhard, M. Desbois, N. Delahaye, S. Viaud, B. Ryffel, H. Yagita, G. Kaplanски, A. Prévost-Blondel, M. Kato, J.L. Schulz, E. Tartour, G. Kroemer, N. Chaput, L. Zitvogel, IL-18 induces PD-1-dependent immunosuppression in cancer, Cancer Res. 71 (2011) 5393–5399, https://doi.org/10.1158/0008-5472.CAN-11-0993.

[46] F. Vidal-Vanaclocha, G. Fantuzzi, L. Mendoza, A.M. Fuentes, M.J. Anasagasti, J. Martin, T. Carrascal, P. Walsh, L.L. Reznikov, S.-H. Kim, D. Novick, M. Rubinstein, C.A. Dinarello, IL-18 regulates IL-1 β-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1, Proc. Natl. Acad. Sci. USA 97 (2000) 734–739, https://doi.org/10.1073/pnas.97.2.734.

[47] K.-E. Kim, H. Song, T.S. Kim, D. Yoon, C. Kim, S.I. Bang, D.Y. Hur, H. Park, D.-H. Cho, Interleukin-18 is a critical factor for vascular endothelial growth factor-enhanced migration in human gastric cancer cell lines, Oncogene 26 (2007) 1468–1476, https://doi.org/10.1038/snj.onc.1209926.

[48] S. Nakamura, T. Otani, R. Okura, Y. Ijiri, R. Motoda, M. Kurimoto, K. Orita, Expression and responsiveness of human interleukin-18 receptor (IL-18R) on hematopoietic cell lines, Leukemia 14 (2000) 1052–1059, https://doi.org/10.1038/sj.leu.2401789.

[49] Y. Ohue, H. Nishikawa, Regulatory t (Treg) cells in cancer: can treg cells be a new therapeutic target? Cancer Sci. 110 (2019) 2080–2089, https://doi.org/10.1111/cas.14069.

[50] M.J. Robertson, J.M. Kirkwood, T.F. Logan, K.M. Koch, S. Kathman, L.C. Kirby, W. N. Bell, L.M. Thurmon, J. Weisenbach, M.M. Dar, A dose-escalation study of recombinant human Interleukin-18 using two different schedules of administration in patients with cancer, Clin. Cancer Res. 14 (2008) 3462–3469, https://doi.org/10.1158/1078-0432.CCR-07-4740.

[51] A.A. Tarhini, M. Millward, P. Mainwaring, R. Kefford, T. Logan, A. Pavlick, S. J. Kathman, K.H. Laubscher, M.M. Dar, J.M. Kirkwood, A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma, Cancer 115 (2009) 859–868, https://doi.org/10.1002/cncr.24100.

[52] D.S. Green, A.T. Nunes, V. David-Ocampo, I.B. Ekwede, N.D. Houston, S.L. Highfill, H. Khuu, D.F. Stroncek, S.M. Steinberg, K.C. Zoon, C.M. Annunziata, A phase 1 trial of autologous monocytes stimulated ex vivo with Sylatron® (Peginterferon alfa-2b) and Actimune® (Interferon gamma-1b) for intra-peritoneal administration in recurrent ovarian cancer, J. Transl. Med. 16 (2018) 196, https://doi.org/10.1186/s12967-018-1569-5.

[53] D.S. Green, F. Ning, A. Duemler, T.G. Myers, K. Trewhitt, I. Ekwede, A. McCoy, N. Houston, J. Lee, S. Lipkowitz, A. Zimmer, M. Pavelova, E.N. Villanueva, L. Smith, A. Blakely, Y. Casablanca, S.L. Highfill, D.F. Stroncek, N. Collins-Johnson, S. Panch, J. Procter, C. Pham, S. Korrapati, S.M. Holland, L.B. Rosen, A.T. Nunes, K. C. Zoon, C.B. Cole, C.M. Annunziata, Intrapereitoneal monocytes plus IFNs as a
novel cellular immunotherapy for ovarian cancer: mechanistic characterization and results from a phase I clinical trial, Clin. Cancer Res. 29 (2023) 349–363, https://doi.org/10.1158/1078-0432.CCR-22-1893.

[54] J. Svoboda, D.J. Landsburg, J. Gerson, S.D. Nasta, S.K. Barta, E.A. Chong, M. Cook, N.V. Frey, J. Shea, A. Cervini, A. Marshall, M. Four, M.M. Davis, J.K. Jadlowsky, A. Chew, E. Pequignot, V. Gonzalez, J.H. Noll, L. Paruzzo, J. Rojas-Levine, G. Plesa, J. Scholler, D.L. Siegel, B.L. Levine, D.L. Porter, S. Ghassemi, M. Ruella, A. Rech, R. M. Leskowitz, J.A. Fraietta, W.-T. Hwang, E. Hexner, S.J. Schuster, C.H. June, Enhanced CAR T-Cell therapy for lymphoma after previous failure, N. Engl. J. Med. 392 (2025) 1824–1835, https://doi.org/10.1056/NEJMoa2408771.

[55] J.-P. Carralot, K. Martin, R.A. Sanchez, R. Meoded, C. Herr, P. Moosman, A. Goepfert, A. Chi, V.J. Pattabiraman, B. Kreft, Abstract 1850: a first-in-class PD1-IL18 immunocytokine (BPT567) targets PD-1+ IL18R+ CD8+ t effector cells enriched in the tumor microenvironment and exhibits potent antitumor efficacy with excellent tolerability, 1850–1850, Cancer Res. 83 (2023), https://doi.org/10.1158/1538-7445.AM2023-1850.

[56] A. Cirella, E. Bolaños, C.A. Di Trani, C.E. de Andrea, S. Sánchez-Gregorio, I. Etxeberria, J. Gonzalez-Gomariz, I. Olivera, D. Brocco, J. Glez-Vaz, C. Luri-Rey, A. Azpilikueta, I. Rodríguez, M. Fernandez-Sendín, J. Egea, I. Eguren, M. F. Sanmamed, B. Palencia, A. Teijeira, P. Berraondo, I. Melero, Intratumoral gene transfer of mRNAs encoding IL12 in combination with decoy-resistant IL18 improves local and systemic antitumor immunity, Cancer Immunol. Res. 11 (2023) 184–198, https://doi.org/10.1158/2326-6066.CIR-22-0373.

[57] O. Kepp, L. Bezu, T. Yamazaki, F. Di Virgilio, M.J. Smyth, G. Kroemer, L. Galluzzi, ATP and cancer immunosurveillance, EMBO J. 40 (2021) e108130, https://doi.org/10.15252/embj.2021108130.

[58] P. Pelegrin, P2X7 receptor and the NLRP3 inflammasome: partners in crime, Biochem. Pharmacol. 187 (2021) 114385, https://doi.org/10.1016/j.bcp.2020.114385.

[59] X.-Y. Li, A.K. Moesta, C. Xiao, K. Nakamura, M. Casey, H. Zhang, J. Madore, A. Lepletier, A.R. Aguilera, A. Sundarrajan, C. Jacoberger-Foissac, C. Wong, T. dela

Cruz, M. Welch, A.G. Lerner, B.N. Spatola, V.B. Soros, J. Corbin, A.C. Anderson, M. Effern, M. Hölzel, S.C. Robson, R.L. Johnston, N. Waddell, C. Smith, T. Bald, N. Geetha, C. Beers, M.W.L. Teng, M.J. Smyth, Targeting CD39 in cancer reveals an extracellular ATP- and Inflammasome-Driven tumor immunity, Cancer Discov. 9 (2019) 1754–1773, https://doi.org/10.1158/2159-8290.CD-19-0541.

[60] I. Perrot, H.-A. Michaud, M. Giraudon-Paoli, S. Augier, A. Docquier, L. Gros, R. Courtois, C. Déjou, D. Jecko, O. Becquart, H. Rispaud-Blanc, L. Gauthier, B. Rossi, S. Chanteux, N. Gourdin, B. Amigues, A. Roussel, A. Bensussan, J.-F. Eliaou, J. Bastid, F. Romagné, Y. Morel, E. Narni-Mancinelli, E. Vivier, C. Paturel, N. Bonnefoy, Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies, e9, Cell Rep. 27 (2019) 2411–2425, https://doi.org/10.1016/j.celrep.2019.04.091.

[61] L. Douguet, S. Janho dit Hreich, J. Benzaquen, L. Seguin, T. Juhel, X. Dezitter, C. Duranton, B. Ryffel, J. Kanellopoulos, C. Delarasse, N. Renault, C. Furman, G. Homerin, C. Fèral, J. Cherfils-Vicini, R. Millet, S. Adriouch, A. Ghinet, P. Hofman, V. Vouret-Craviari, A small-molecule P2RX7 activator promotes antitumor immune responses and sensitizes lung tumor to immunotherapy, Nat. Commun. 12 (2021) 653, https://doi.org/10.1038/s41467-021-20912-2.

[62] S. Janho Dit Hreich, P. Hofman, V. Vouret-Craviari, The role of IL-18 in P2RX7-mediated antitumor immunity, Int. J. Mol. Sci. 24 (2023) 9235, https://doi.org/10.3390/ijms24119235.

[63] C. Valero, M. Lee, D. Hoen, K. Weiss, D.W. Kelly, P.S. Adusumilli, P.K. Paik, G. Plitas, M. Ladanyi, M.A. Postow, C.E. Ariyan, A.N. Shoushtari, V. P. Balachandran, A.A. Hakimi, A.M. Crago, K.C. Long Roche, J.J. Smith, I. Ganly, R. J. Wong, S.G. Patel, J.P. Shah, N.Y. Lee, N. Riaz, J. Wang, A. Zehir, M.F. Berger, T. A. Chan, V.E. Seshan, L.G.T. Morris, Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors, Nat. Commun. 12 (2021) 729, https://doi.org/10.1038/s41467-021-20935-9.