IL-17A functions and the therapeutic use of IL-17A and IL-17RA targeted antibodies for cancer treatment

Song, Minju; Liang, Jie; Wang, Luoyang; Li, Wei; Jiang, Shaojun; Xu, Su; Tang, Lei; Du, Qiang; Liu, Guixian; Meng, Haining; Zhai, Dongchang; Shi, Shangheng; Yang, Yanyan; Zhang, Li; Zhang, Bei

doi:10.1016/j.intimp.2023.110757

Cited by 13 publications

(4 citation statements)

References 175 publications

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“…We can evaluate the relationship, mechanism and outcome prediction between IL‐17RA and Treg/MDSC in clinical CRC tissues in the future. In addition, we plan to explore the IL‐17/IL‐17RA pathway as a therapeutic target using humanized antibodies (secukinumab, ixekizumab, brodamulab) or small molecule inhibitors (S011806, LY3509754, LEO 153339) in mouse model and clinical trial 55,56 …”

Section: Discussionmentioning

confidence: 99%

Decreased interleukin‐17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice

Jiang,

Lin,

Chang

et al. 2024

Cancer Medicine

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BackgroundInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine that plays a vital role in the promotion of tumorigenesis in various cancers, including colorectal cancer (CRC). Based on current evidence, IL‐17 binds to interleukin‐17 receptor A (IL‐17RA); however, the role of IL‐17RA has not been elucidated in previous studies on CRC. In this study, we explored the role of IL‐17RA in human CRC tissues and the progression of CRC in humans and mice.MethodsThe expressions of IL‐17RA and epithelial‐mesenchymal transition (EMT)‐related genes were examined in CRC cells and tissue samples by quantitative real‐time polymerase chain reaction. The role of IL‐17RA in pathogenesis and prognosis was evaluated using a Chi‐squared test, Kaplan–Meier analysis, univariate, and multivariate Cox regression analysis in 133 CRC patients. A tumor‐bearing mice model was executed to evaluate the role of IL‐17RA in tumor growth, vascularity and population of infiltrating immune cells.ResultsIL‐17RA expression was found to be significantly higher in CRC tissues than in adjacent normal tissues. The expression of IL‐17RA in Stage IV patients was significantly higher than that in Stages I and II patients. Patients with high IL‐17RA expression exhibited significantly worse overall and CRC‐specific survival than those with low IL‐17RA expression. Functional assessment suggested that the knockdown of IL‐17RA expression distinctly suppressed cellular proliferation, migration, invasion, and EMT‐related gene expression. In a tumor‐bearing mouse model, decreased IL‐17RA expression significantly repressed tumor growth and vascularity and reduced the population of regulatory T cells (Tregs) and myeloid‐derived suppressor cells (MDSCs).ConclusionReduced IL‐17RA expression also suppressed cellular proliferation, migration, and invasion, and the expression of EMT genes. Knockdown of IL‐17RA inhibited tumor growth and vascularity and decreased the population of Tregs and MDSCs in mouse tumors. Overall, IL‐17RA expression was identified to be independently associated with the prognosis of patients with CRC.

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Section: Discussionmentioning

confidence: 99%

Decreased interleukin‐17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice

Jiang,

Lin,

Chang

et al. 2024

Cancer Medicine

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“…Our study not only validated the increased expression of IL-17A and IL-17C in HGSOC compared with FTE tissues, but also revealed that the administration of IL-17A to the conditioned media significantly increased cell viability in WT organoids, while having no significant effect on TP53 + RAD51D-KD organoids. Regarding the underlying mechanism for the IL-17 signaling pathway to manipulate tumor progression, previous studies demonstrate that it directly impacts these cells by overseeing the control of inflammatory factors, spurring tumor cell proliferation, fostering the epithelial-to-mesenchymal cell transformation (EMT), upregulating MMP, attracting inflammatory cells to tumor sites, and thwarting the processes of autophagy and cell death [39,40,73,74]. IL-17A upregulated CXCL1 secretion in breast cancer cells, resulting in the enhanced migration, invasion, and increased expression of pAKT and pNF-κB [75].…”

Section: Discussionmentioning

confidence: 99%

“…We also confirmed the upregulation of CXCL1 in TP53 + RAD51D-KD by using qRT-PCR and ELISAs in our study. Given that various IL-17-related inhibitors and IL-17R-related inhibitors have entered clinical trial testing in recent years, a limitation of our study is the lack of investigation of the effects of these medications on TP53 ± RAD51D organoids [74]; however, our organoid model serves as a faithful physiological in vitro platform for future drug screening studies.…”

Section: Discussionmentioning

confidence: 99%

Human Fallopian Tube-Derived Organoids with TP53 and RAD51D Mutations Recapitulate an Early Stage High-Grade Serous Ovarian Cancer Phenotype In Vitro

Dai,

Xu,

Gong

et al. 2024

IJMS

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RAD51D mutations have been implicated in the transformation of normal fallopian tube epithelial (FTE) cells into high-grade serous ovarian cancer (HGSOC), one of the most prevalent and aggressive gynecologic malignancies. Currently, no suitable model exists to elucidate the role of RAD51D in disease initiation and progression. Here, we established organoids from primary human FTE and introduced TP53 as well as RAD51D knockdown to enable the exploration of their mutational impact on FTE lesion generation. We observed that TP53 deletion rescued the adverse effects of RAD51D deletion on the proliferation, stemness, senescence, and apoptosis of FTE organoids. RAD51D deletion impaired the homologous recombination (HR) function and induced G2/M phase arrest, whereas concurrent TP53 deletion mitigated G0/G1 phase arrest and boosted DNA replication when combined with RAD51D mutation. The co-deletion of TP53 and RAD51D downregulated cilia assembly, development, and motility, but upregulated multiple HGSOC-associated pathways, including the IL-17 signaling pathway. IL-17A treatment significantly improved cell viability. TP53 and RAD51D co-deleted organoids exhibited heightened sensitivity to platinum, poly-ADP ribose polymerase inhibitors (PARPi), and cell cycle-related medication. In summary, our research highlighted the use of FTE organoids with RAD51D mutations as an invaluable in vitro platform for the early detection of carcinogenesis, mechanistic exploration, and drug screening.

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“…Furthermore, IL‐17 inhibitors have shown profound therapeutic potential in addressing irAEs, such as intestinal issues, arthropathy and psoriasis, in NSCLC, although their use may potentially promote tumour immune escape. 183 , 184 Further clinical trials are underway in NSCLC to assess the effectiveness of tocilizumab in managing migrating irAEs (NCT04691817 NCT04940299). Despite the limited research data on the use of cytokine inhibitors for irAEs, the advancement of specialised cytokine treatments remains promising.…”

Section: Management Strategies To Abrogate Iraes Of Icis In Nsclcmentioning

confidence: 99%

Immune‐related adverse events in non‐small cell lung cancer: Occurrence, mechanisms and therapeutic strategies

Lin,

Xie,

Yao

et al. 2024

Clinical & Translational Med

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The emergence of immune checkpoint inhibitors (ICIs) has heralded a transformative era in the therapeutic landscape of non‐small cell lung cancer (NSCLC). While ICIs have demonstrated clinical efficacy in a portion of patients with NSCLC, these treatments concurrently precipitate a spectrum of immune‐related adverse events (irAEs), encompassing mild to severe manifestations, collectively posing a risk of significant organ damage. Consequently, there exists an imperative to augment our comprehension of the pathophysiological underpinnings of irAEs and to formulate more efficacious preventive and ameliorative strategies. In this comprehensive review, we delineate the clinical presentation of organ‐specific irAEs in patients with NSCLC and provide an in‐depth analysis of recent advancements in understanding the mechanisms driving ICI‐induced toxicity. Furthermore, we discuss potential strategies and targets for ameliorating these irAEs. Ultimately, this review aims to furnish valuable insights to guide further research endeavours in the context of irAEs in NSCLC patients.

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IL-17A functions and the therapeutic use of IL-17A and IL-17RA targeted antibodies for cancer treatment

Cited by 13 publications

References 175 publications

Decreased interleukin‐17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice

Decreased interleukin‐17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice

Human Fallopian Tube-Derived Organoids with TP53 and RAD51D Mutations Recapitulate an Early Stage High-Grade Serous Ovarian Cancer Phenotype In Vitro

Immune‐related adverse events in non‐small cell lung cancer: Occurrence, mechanisms and therapeutic strategies

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