Interleukin-1Beta Signalin in Non-Small Cell Lung Cancer: History
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Dani Ran Castillo
,
Won Jin Jeon
,
Daniel Park
,
Bryan Pham
,
Chieh Yang
,
Bowon Joung
,
Jin Hyun Moon
,
Jae Lee
,
Esther G. Chong
,
Kiwon Park
,
Mark E. Reeves
,
Penelope Duerksen-Hughes
,
Hamid R. Mirshahidi
,
Saied Mirshahidi

Targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies; further, there is an unmet need to identify prognostic biomarkers of response to treatment. Inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations and offer insight into the continued search for prognostic biomarkers.

  • ICIs
  • IL-1β
  • therapeutic resistance
  • inflammation
  • signaling
  • NSCLC
  • tumor microenvironment

1. Introduction

Lung cancer remains the leading cause of cancer-related mortality and the second most common malignancy worldwide[1]. For non-small cell lung cancer (NSCLC), initial management begins with searching for targetable drivers such as EGFR, ALK, ROS-1, NTRK, RET, NRG or BRAF, MET. Unfortunately, treatment options for patients without such targetable mutations are limited[2]. Dysregulated inflammatory conditions contribute to lung carcinogenesis by causing protumor inflammation, tumor suppression, and the activation of oncogenes[1]. Further, the tumor microenvironment (TME) is becoming recognized as a key factor in carcinogenesis and is a topic of great interest for seeking management options for NSCLC without targetable mutations[3]. Immunomodulators targeting the PD-1/PD-L1 axis have had promising results, but therapeutic resistance is common and challenging for clinicians. Recent advances in understanding the IL-1β/PD-1/PD-L1 pathway have prompted attempts to utilize combinatorial strategies that involve IL-1β inhibitors together with ICIs. To identify biomarkers that predict the ICI response in tumors without actionable mutations and provide a solution for patients with actionable mutations who develop resistance to currently approved targeted therapies, understanding the crosstalk that occurs within the IL-1β/PD-1/PD-L1 pathway and the TME alterations that arise when ICIs are combined with IL-1β inhibitors is crucial.

2. Il-1β Signaling in NSCLC

The TME is altered by many immune factors, and recent studies have shown that the TME of lung cancer is proinflammatory[4]. Due to the relationship between chronic inflammatory states and cancer, serum levels of IL-1β, IL-6, IL-8 [5] have been studied as potential biomarkers of malignancy. For example, patients with breast, lung, cervical, hepatocellular, and gastric cancer tumor cells revealed increased levels of IL-1β alleles[6]. In general, the expression of IL-1β is induced by the presence of stressful stimuli such as hypoxia, inflammation, infection, which induces toll-like receptors (TLRs) to stimulate tumor necrosis factor (TNF). Inactive pro-IL1β is activated by intracellular protein complexes, known as inflammasomes, and then cleaved by caspase-1 (also known as IL-1β-converting enzyme (ICE)) into its active form. Immune cells involved in tumor suppression, T cells, dendritic cells (DCs), epithelial cells, neutrophils, macrophages, and other antigen-presenting cells (APCs) express IL-1 receptors (IL-1R and IL-1R2) which interact with IL-1β (Figure 1). IL-1β signaling recruits myeloid differentiation primary response-88 (MyD88) and IL-1R associated kinases (IRAKs), which directly interact with TNF receptor-associated factor 6 (TRAF6). This activates the mitogen-activated protein kinase (MAPK) pathway and (nuclear factor kappa B) NF-κB, thus activating downstream inflammatory pathways and promoting the unchecked growth of malignant cells and inhibiting apoptosis[7].
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Figure 1. Mechanism of the IL-1β pathway and its downstream effects. Legend: GSDMD—gasdermin D; IRAK—IL-1 receptor-associated kinase; MYD88—myeloid differentiation primary response 88; TRAF6—tumor necrosis factor receptor associated factor 6; MAPK—mitogen-activated protein kinase; IkB—inhibitor of nuclear factor kappa B; NF-kB (nuclear factor kappa B); AP-1—activator protein 1.
Chronic inflammation has been linked to an increased risk of cancer by providing survival signals, suppressing T-cells’ effector functions, inducing angiogenesis, and promoting invasion and metastasis[8][9]. The active form of IL-1β induces protumor inflammation, tumorigenesis, immune invasion, and metastasis (Figure 2)[8] [10][9]. IL-1β may also have a positive feedback loop, perpetuating the course of the cancer. Within the TME, tumor cells are the source of chronic inflammation, and IL-1β becomes an upstream regulator, altering immunologic responses, hormonal signaling, neovascularization, and enhancing metastatic potential through downstream pathways such as NF-κB/MAPK/Protein Kinase B (AKT)/Wnt/β-catenin.
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Figure 2. The effects of IL-1β on the tumor microenvironment. The figure depicts immunoregulatory cells altering the TME via secretion of IL-1β, which promote protumor changes including angiogenesis, immune suppression, and metastasis. Legend. TME—tumor microenvironment; APC—antigen-presenting cell; IL-1β—interferon 1-beta.
The role of IL-1β in cancer is complex, and its ability to directly alter the TME has been studied in the preclinical setting. For example, an increased expression of IL-1β has been shown to promote the accumulation of myeloid-derived suppressor cells (MDSCs), decrease the number of natural killer (NK) cells, and increase tumor size [10][11]. The levels of MDSCs, our body’s major suppressors of immunological responses to tumors, are significantly increased in the TME, which leads to the maintenance and acceleration of tumor growth and metastasis[8]. An increased accumulation of MDSCs results in the expansion of CD4+ CD25+ Foxp3+ regulatory T cells (Tregs), leading to downregulation of the antitumor capability of NK and cytotoxic T cells. IL-1β also functions as a chemoattractant to recruit tumor-associated macrophages (TAMs) by attaching monocyte chemoattractant protein (MCP-1) on tumor cells[12]. This cascade further potentiates IL-1β production via TAMs and triggers inflammasomes to promote further tumor growth[11].
Furthermore, IL-1β has been implicated in the promotion of angiogenesis in several types of malignancies, such as melanoma and fibrosarcoma, potentiating their metastatic potential[6][13][14]. This is due to its ability to induce the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor (TGF-αβ), platelet-derived endothelial growth factor (PDGF), interleukin-8 (IL-8, also known as CXCL8), and fibroblast growth factors (FGF). They mediate the migration and proliferation of endothelial cells to expand the existing vascular system, which is necessary for the delivery of nutrients and oxygen to rapidly growing tumor cells[13]. IL-1β also increases the expression of matrix metalloproteinases (MMPs), which degrade extracellular matrix (ECM) proteins, facilitating the migration and invasion of tumor cells into surrounding tissues[8][13]. MMPs further promote angiogenesis by releasing sequestered pro-angiogenic factors from the ECM, making them available to surrounding cells. In addition, in lung cancer, exposure to IL-1β decreases phosphatase and tensin homolog (PTEN) expression, phosphoinositide 3-kinase (PI3K)/AKT signaling activation, and the induction of epithelial–mesenchymal transition (EMT), conferring primary lung carcinoma cells with the ability to mobilize, invade, and damage distant sites, leading to angiogenesis [15][16][17].
Specifically, for NSCLC, IL-1β has a multifaceted impact on the development and progression of the disease. Patients with NSCLC have been found to have elevated levels of IL-1β in plasma and IL-1β mRNA expression, and serum IL-1β has been associated with worse prognosis[14][18][19]. In NSCLC, IL-1β potentiates accelerated neoplastic progression by repressing miR-101 expression through the cyclooxygenase 2 (COX2)/HIF1α pathway[18]. Tumor-derived IL-1β activates γδT-cells, which in turn secrete IL-17. The secretion of IL-17 causes neutrophils to increase inducible nitric oxide synthase (iNOS) and suppress anti-tumor CD8+ T cells, leading to an increase in metastatic potential[20]. In lung cancer, it has also been shown that commensal bacteria promote IL-1β production from local macrophages, inducing tumor cell proliferation and inflammation[21].
Despite recent advances in targeted therapies for NSCLC patients with specific genetic mutations, the lack of robust response has been a challenge for clinicians[22]. IL-1β has been implicated in the development of therapeutic resistance. For example, it has been observed that varying levels of IL-1β are present in therapy-resistant patients[8][23]. Thus, the heterogeneity of serum IL-1β levels may explain the variability of response to treatment options in NSCLC[23][24]. Additionally, mutations found in lung cancer cells are associated with the IL-1β axis, making it a potential target for therapy[15]. BRAF (V600E) mutations are rare in NSCLC but can occur in up to 2% of cases[25]. Treatment of these neoplasms with BRAF inhibitors (BRAFi) has been shown to increase dendritic cell-mediated IL-1β production, worsening the inflammatory positive feedback loop and promoting resistance. Hajek et al. demonstrated that the combination of dabrafenib with vemurafenib or trametinib, BRAFis used in melanoma and NSCLC patients with BRAFV600E mutation, strongly upregulated IL-1β production in myeloid mouse APCs due to BRAFi-induced activation of the inflammasome leading to caspase-8 activation and pro-IL-1β processing. Alternative mechanisms explain BRAFi resistance by a cytokine-signaling network involving TAM-derived IL-1β, cancer-associated fibroblasts (CAFs)-derived CXCR2 ligands, and PTEN inactivation[26]. Still, the mechanism of resistance to BRAFi and BRAFi combinatorial regimens remains an unmet area of further study. Given that IL-1β production affects PTEN, it is reasonable to hypothesize that IL-1β inhibitors may aid in combating resistance to BRAFi. Therefore, further studies are warranted to explore the potential of IL-1β inhibitors in combination with BRAFi in NSCLC patients with BRAF mutations.
The role of IL-1β in the development of resistance to treatment in NSCLC is further implicated in current studies with bortezomib and EGFR inhibitors. Davies et al. showed that bortezomib, a proteasome inhibitor that partially inhibits NF-κB, is not effective as a single agent in the treatment of NSCLC[27]. Further investigation revealed that the inhibition of NF-κB signaling was associated with an increase in IL-1β production and enhanced tumorigenesis in the lungs. Interestingly, McLeod et al. demonstrated that dual blockade with an IL-1R antagonist (anakinra) and bortezomib resulted in increased therapeutic efficacy by reducing lung tumor burden[28]. These findings suggest that the inefficiency of monotherapy with NF-κB inhibitors in NSCLC may be due to the potentiation of neutrophil-dependent production of IL-1β, leading to enhanced pulmonary carcinogenesis. The study also highlights the role of IL-1β in resistance to currently available treatment modalities and suggests that combined NF-κB and IL-1β targeted treatments may lead to reduced tumor formation and growth [12][28]. The recent study conducted by Yuan et al. revealed that blocking the IL-1β pathways resulted in an upsurge in cytotoxic CD8+ T cell infiltration and a reduction in the protumor immunosuppressive response. Additionally, this treatment proved to be highly effective in inhibiting the activation of the NF-κB and STAT3 pathways[29].
In addition, Huang et al. found that IL-1β upregulates EH domain-containing protein 1 (EHD1) expression, which activates the PTEN/PI3K/AKT signaling pathway, leading to off-site EGFR-TKI resistance in NSCLC. Interestingly, the inhibition of the IL-1β/EHD1/TUBB3 axis has shown promising results in overcoming EGFR-TKI resistance[15]. These findings suggest that inhibition of the IL-1β/EHD1 signaling pathway may be a target for patients who develop EGFR-TKI resistance. Overall, the combinatorial, targeted strategies toward the IL-1β axis may be a solution for NSCLC patients with actionable mutations who have developed resistance to currently approved targeted therapies.

3. Conclusions

Both preclinical and clinical studies suggest that the IL-1β/PD-1/PD-L1 pathway plays a crucial role in carcinogenesis of NSCLC and interacts within the TME. IL-1β signaling may be associated with resistance to therapy and represents a novel therapeutic target for NSCLC. However, further studies are warranted to fully elucidate the underlying mechanisms and determine the optimal combination regimens. As research into the IL-1β pathway continues to progress, it is hoped that the development of new therapeutic strategies will lead to standardized prediction models and biomarkers of response, and ultimately, improved outcomes for patients with NSCLC.

This entry is adapted from the peer-reviewed paper 10.3390/ijms241411547

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