Decreased expression of JAK1 associated with immune infiltration and poor prognosis in lung adenocarcinoma

Cai, Jin-lian; Deng, Hong; Luo, Linlin; You, Luxia; Liao, Huitian; Zheng, Yan

doi:10.18632/aging.202205

Cited by 7 publications

(6 citation statements)

References 45 publications

(35 reference statements)

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“…Moreover, in Part 1b/Groups A-1/A-2, 4 patients achieved a PR with no remarkable efficacy observed in any one tumor type treated with itacitinib plus pembrolizumab. In a database analysis study of lung adenocarcinoma transcriptome profiles, JAK1 expression was positively correlated with immune-cell infiltration, suggesting a potential role of JAK1 in the immune response ( 25 ). In a noncancer but immune-related setting, JAK1 signaling has been implicated in the immune response in acute GVHD, and treatment with itacitinib demonstrated clinical benefit in a phase I study ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study

Munster,

Iannotti,

Cho

et al. 2023

Cancer Research Communications

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Purpose: This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor]. Experimental Design: Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks). Results: A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR. Conclusions: Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors. Significance: PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations.

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Section: Discussionmentioning

confidence: 99%

Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study

Munster,

Iannotti,

Cho

et al. 2023

Cancer Research Communications

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“…Previous studies have shown that abnormal activation of the IL-6/STAT3 pathway could induce the expression of PD-L1, enhance tumor cell proliferation, and inhibit tumor cell apoptosis in NSCLC ( 30 , 31 ). In addition, Cai et al reported that decreased expression of JAK1 was associated with immune infiltration and a poor prognosis in LUAD tissues ( 32 ). While the specific regulatory mechanism of RHEX involved in JAK-related signaling pathways needs to be verified through more detailed experiments, the low expression group was mainly enriched in multiple gene sets with well-established roles in NSCLC development, including G2M_CHECKPOINT, MYC_TARGETS_V1/V2, E2F_TARGETS, DNA_REPAIR, MTORC1_SIGNALING, and GLYCOLYSIS.…”

Section: Discussionmentioning

confidence: 99%

Identification of RHEX as a novel biomarker related to progression and immunity of non-small cell lung carcinoma

Xu¹,

Dai²,

Zeng³

et al. 2021

Transl Cancer Res TCR

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Background: The therapeutic response and prognosis of patients with non-small cell lung carcinoma (NSCLC) are widely related to immunity. To improve the prognosis of patients and provide reliable information to guide appropriate personalized treatment strategies, it is necessary to identify reliable prognostic or predictive indicators closely related to tumor phenotype and immune traits in NSCLC.Methods: Based on The Cancer Genome Atlas (TCGA)-NSCLC mRNA expression profile data, a novel approach combining differential gene expression analysis, single-sample gene set enrichment analysis (ssGSEA), and weighted gene co-expression network analysis (WGCNA) was used to screen hub genes.Subsequently, the regulator of hemoglobinization and erythroid cell expansion (RHEX) was identified as a key gene using the log-rank test and confirmed in the ArrayExpress database. The relationship between RHEX and clinicopathological parameters was analyzed using the Wilcoxon rank-sum test. More importantly, through gene set enrichment analysis (GSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithms, and with reference to the Tumor IMmune Estimation Resource (TIMER) database, we explored the relevant pathways of RHEX and its relationship with tumor-infiltrating immune cells (TICs). Finally, we depicted the association between RHEX and immunomodulators in the TCGA and a web portal TISIDB. Results:The RHEX mRNA expression levels in tumor tissues were lower than those in normal tissues and declined with the progression of NSCLC. Meanwhile, RHEX overexpression was associated with high immune infiltration levels and a favorable clinical prognosis. RHEX may participate in tumor microenvironment (TME) regulation through multiple tumor-immune related pathways, especially the JAK-STAT signaling pathway. Furthermore, RHEX expression affected the infiltrating abundance of multiple TICs and positively correlated with most of the immunomodulators in NSCLC. Conclusions:Our study is the first to propose that RHEX is an immune-related gene with prognostic value in NSCLC and reveals the underlying mechanism between RHEX and tumor-immune system interactions. These results ultimately provide guidance for prognosis and immunotherapy for NSCLC patients.

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“…Matrigel (25 µl Matrigel was diluted in 25 µl serum-free medium and cultured at 37˚C for 2 h)-coated Transwell chambers (BD Biosciences) were used for cell invasion assessment. A total of 1x10 5 LUAD cells resuspended in FBS-free medium were placed into the top chamber, while 600 µl of culture medium containing 15% FBS were added into the bottom chamber. Following incubation at 37˚C for 48 h, cells on the top of the filter were removed using cotton swabs, and cells on the bottom were fixed in 4% paraformaldehyde and then stained with 1% crystal violet (Beijing Solarbio Science & Technology Co., Ltd.) for 10 min at room temperature.…”

Section: Reverse Transcription-quantitative Pcr (Rt-qpcr)mentioning

confidence: 99%

“…The incidence of LUAD has increased in recent years, with the 5-year survival rate value as low as 15% (2). A number of genes have been reported to be dysregulated and to be involved in LUAD progression; however, the mechanisms underlying the occurrence and development of LUAD remain largely unknown (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

ATIC facilitates cell growth and migration by upregulating Myc expression in lung adenocarcinoma

Niu

Zeng

et al. 2022

Oncol Lett

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5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a catalysing enzyme in the de novo purine biosynthetic pathway, has been previously reported to be upregulated and to participate in myeloma and hepatocellular carcinoma progression. In the present study, by using bioinformatics technology, a higher ATIC expression was identified in lung adenocarcinoma (LUAD) tissues than in normal tissues, and ATIC expression was found to be positively associated with Myc expression in LUAD tissues. In addition, the role of ATIC in modulating the growth and migration of LUAD cells was explored and the involvement of Myc was revealed. ATIC expression in 56 paired LUAD and tumour adjacent non-cancerous tissues was assessed using reverse transcription-quantitative PCR and western blot analysis. Pearson's correlation analysis was applied to evaluate the correlation between ATIC and Myc expression levels in LUAD tissues. A rescue experiment was performed to explore the role of ATIC/Myc in regulating the growth, migration and invasion of HCC827 and NCI-H1435 cells. It was demonstrated that ATIC was overexpressed in LUAD tissues, particularly in advanced-stage LUAD, and was predicted to be associated with an advanced TNM stage, a higher lymph node metastasis rate, poor tissue differentiation and a lower overall survival rate. ATIC overexpression promoted cell growth, migratory and invasive capacities, whereas this effect was abrogated by Myc knockdown in the HCC827 and NCI-H1435 cells. On the whole, the present study demonstrates that ATIC promotes LUAD cell growth and migration by increasing Myc expression.

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Decreased expression of JAK1 associated with immune infiltration and poor prognosis in lung adenocarcinoma

Cited by 7 publications

References 45 publications

Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study

Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study

Identification of RHEX as a novel biomarker related to progression and immunity of non-small cell lung carcinoma

ATIC facilitates cell growth and migration by upregulating Myc expression in lung adenocarcinoma

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