Intratumoral IL-1R1 expression delineates a distinctive molecular subset with therapeutic resistance in patients with gastric cancer

Zhang, Puran; Gu, Yun; Fang, Hanji; Cao, Yifan; Wang, Jieti; Liu, Hao; Zhang, Heng; He, Li; He, Hongyong; Li, Ruochen; Lin, Chao; Xu, Jiejie

doi:10.1136/jitc-2021-004047

Cited by 15 publications

(12 citation statements)

References 50 publications

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“…Tumor-associated NLRP3/IL-1β signaling gives rise to an immunosuppressive environment characterized partly by the regulation of M2-polarized TAMs and a reduction in antitumor CD8 + T cells [81]. These results indicate the relationship of the IL-1 signaling pathway to particular genotypes and molecular properties of cancer [82], signifying the importance of IL-1β in modifying the TME.…”

Section: Pyroptosis In Cancer Therapies Immunotherapymentioning

confidence: 84%

Induction of pyroptotic cell death as a potential tool for cancer treatment

et al. 2022

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Cancer is a complex pathological disease and the existing strategies for introducing chemotherapeutic agents have restricted potential due to a lack of cancer cell targeting specificity, cytotoxicity, bioavailability, and induction of multi-drug resistance. As a prospective strategy in tackling cancer, regulating the inflammatory pyroptosis cell death pathway has been shown to successfully inhibit the proliferation and metastasis of various cancer cell types. Activation of inflammasomes such as the NLRP3 results in pyroptosis through cleavage of gasdermins, which forms pores in the cell membranes, inducing membrane breakage, cell rupture, and death. Furthermore, pyroptotic cells release pro-inflammatory cytokines such as IL-1β and IL-18 along with various DAMPs that prime an auxiliary anti-tumor immune response. Thus, regulation of pyroptosis in cancer cells is a way to enhance their immunogenicity. However, immune escape involving myeloid-derived suppressor cells has limited the efficacy of most pyroptosis-based immunotherapy strategies. In this review, we comprehensively summarize the cellular and molecular mechanisms involved in the inflammasome-mediated pyroptosis pathways in cancer cells, exploring how it could modulate the tumor microenvironment and be beneficial in anti-cancer treatments. We discuss various existing therapeutic strategies against cancer, including immunotherapy, oncolytic virus therapy, and nanoparticle-based therapies that could be guided to trigger and regulate pyroptosis cell death in cancer cells, and reduce tumor growth and spread. These pyroptosis-based cancer therapies may open up fresh avenues for targeted cancer therapy approaches in the future and their translation into the clinic.

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Section: Pyroptosis In Cancer Therapies Immunotherapymentioning

confidence: 84%

Induction of pyroptotic cell death as a potential tool for cancer treatment

et al. 2022

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“…When a Gene Ontology analysis was done by us using these genes, ‘macrophage inhibitory factor signalling’ was the top biological process ( Supplementary Figure 8A ). Recent studies have implicated IL1R1-related signalling in M2 tumour-associated macrophage (TAM) infiltration in tumours(Chen et al, 2023; Zhang et al, 2022). In our data, we had observed consistent change in IL1R1 and IL1B in long versus short telomere tumours and also noted that IL1 signalling has been widely implicated with TAM infiltration in multiple cancers (Carmi et al, 2009; Chittezhath et al, 2014; Lappano et al, 2020; Mantovani et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Telomere length sensitive regulation of Interleukin Receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment

Mukherjee

Singh

Sharma

et al. 2021

Preprint

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The role of telomeres in sustained tumor growth is well understood. However, mechanisms of how telomeres might impact the tumor microenvironment (TME) are not clear. Upon examining tumor associated macrophages (TAMs) in 94 hormone-negative (triple-negative) breast cancer (TNBC) cases we found infiltration of TAMs to be telomere sensitive: Tumors with relatively short telomeres had higher abundance of TAM and vice versa. This observation was replicated across TNBC clinical tissue, patient-derived organoids, tumor xenografts and cancer cells with long/short telomeres. Mechanistically, we demonstrate that non-telomeric binding of TRF2, a telomere-repeat-binding-factor; at the interleukin receptor IL1R1 promoter directly activates IL1R1 through recruitment of the histone-acetyl-transferase p300 and consequent H3K27 acetylation. Interleukin-1signaling could be induced in TRF2-high cells through ligands IL1A/B, but not TNFα, and abrogated by the receptor antagonist IL1RA, supporting specificity of the TRF2-IL1R1axis. TRF2 binding at the IL1R1 promoter was mediated by G-quadruplex motifs and was sensitive to telomere length – thereby establishing telomere-length-dependent regulation of IL1R1 and IL1-mediated TAM infiltration in cancers. Our results reveal a heretofore unknown function of telomeres in interleukin signaling and anti- tumor immune response, through non-telomeric TRF2. Therefore, we propose telomere length as a novel biomarker underlying patient-specific response to cancer immunotherapy.

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“…In the present study, Lut treatment downregulated IL‐1R1 expression. Recent studies have reported that high expression of IL‐1R1 in GC predicts poor prognosis and reactivity to 5‐fluorouracil adjuvant chemotherapy and immune checkpoint blockade, suggesting that IL‐1R1 may be an important target for Lut intervention in GC (Zhang, Gu, et al, 2022). These results have potential applications; however, further studies are necessary to identify the targets of Lut.…”

Section: Discussionmentioning

confidence: 99%

Antitumor effect of luteolin proven by patient‐derived organoids of gastric cancer

Hao

Ning

et al. 2023

Phytotherapy Research

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Luteolin (Lut) has been shown to inhibit gastric cancer (GC); however, its efficacy compared to other clinical drugs has not been examined in human samples. This study aimed to elucidate the antitumor activity of Lut in GC patient‐derived organoids (PDOs). PDOs were established from GC cancer tissues, and the characterization of tissues and PDOs was performed using whole‐exome sequencing. Drug sensitivity tests were performed by treating PDOs with Lut, norcantharidin (NCTD), and carboplatin (CP). RNA sequencing of PDOs was performed to elucidate the antitumor mechanism of Lut, which was further verified in three GC cell lines. Eleven PDOs were successfully constructed, and were highly consistent with the pathophysiology and genetic changes in the corresponding tumors. The IC50s of Lut, NCTD, and CP of PDOs were 27.19, 23.9, and 37.87 μM, respectively. Lut treatment upregulated FOXO3, DUSP1, and CDKN1A expression and downregulated IL1R1 and FGFR4 expression in GC cell lines, which was consistent with the results of PDOs. We demonstrate that Lut exerted stronger antitumor effects than CP, but a similar effect to that of NCTD, which was obtained in an in vitro PDO system. Additionally, Lut exerted varying degrees of antitumor effects against the PDOs, thereby indicating that PDO may be a useful preclinical drug screening tool for personalized treatment.

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Intratumoral IL-1R1 expression delineates a distinctive molecular subset with therapeutic resistance in patients with gastric cancer

Cited by 15 publications

References 50 publications

Induction of pyroptotic cell death as a potential tool for cancer treatment

Induction of pyroptotic cell death as a potential tool for cancer treatment

Telomere length sensitive regulation of Interleukin Receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment

Antitumor effect of luteolin proven by patient‐derived organoids of gastric cancer

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