Systematic assessment of the clinicopathological prognostic significance of tissue cytokine expression for lung adenocarcinoma based on integrative analysis of TCGA data

Abstract

Dysregulated intratumoral immune reactions are shaped by complex networks of cytokines, which coordinate with tumor cells to determine tumor progression and aggressiveness. In lung adenocarcinoma (LUAD), the role of intratumoral cytokine gene expression for stratifying prognosis has not been systematically investigated. Using high-dimensional datasets of cancer specimens from clinical patients in The Cancer Genome Atlas (TCGA), we explored the transcript abundance and prognostic impact of 27 clinically evaluable cytokines in 500 LUAD tumor samples according to clinicopathological features and two common driver mutations (EGFR and KRAS). We found that reduced expression of IL12B presented as the single prognostic factor for both poor overall survival (OS) and recurrence free survival (RFS) with high hazard ratios. Moreover, we identified that elevated expression of IL6, CXCL8 and CSF3 were additional independent predictors of poor RFS in LUAD patients. Their prognostic significance was further strengthened by their ability to stratify within clinicopathological factors. Notably, we prioritized high risk cytokines for patients with or without mutations in EGFR and KRAS. Our results provide integrative associations of cytokine gene expression with patient survival and tumor recurrence and demonstrate the necessity and validity of relating clinicopathological and genetic disposition factors for precise and personalized disease prognosis.

Low Expression of IL-15 and NKT in Tumor Microenvironment Predicts Poor Outcome of MYCN-Non-Amplified Neuroblastoma

“…We are the first to show that lower IL-15 expression is significantly associated with worse EFS and OS in NBL patients. This is in line with previous reports that IL-15 is an independent prognostic marker for patients with prostate cancer [ 38 ], breast cancer [ 39 ], and lung adenocarcinoma [ 40 ]. We are also the first to report the association between IL-15 and MYCN, although the molecular mechanism remains obscure.…”

The Diverse Roles of Heme Oxygenase-1 in Tumor Progression

“…The tumor stroma is a rich source of cytokines, soluble proteins which act as signaling molecules between cells, creating a complex crosstalk within the stroma and tumor cells ( 76 ). The cytokine milieu is different between cancers ( 27 , 77 ), which contributes to the heterogeneity of the TME through influencing recruitment and/or polarization of cells such as is observed with TAM ( 27 ) and Treg ( 78 ) populations. Specifically in relation to HO-1 expression, IL-1α and TNF-α, which have pro-inflammatory effects, have been demonstrated to induce HMOX1 gene expression through a pathway involving protein kinase C (PKC), Ca 2+ signaling and phospholipase A2 (PLA2) ( 79 ), which directs HMOX1 expression through the transcription factor AP-1 binding the AP-1 binding site in the HMOX1 promoter ( 80 ).…”

Identification and analysis of genes associated with lung adenocarcinoma by integrated bioinformatics methods

“…However, a comprehensive understanding of the underlying mechanisms of LUAD metastasis is still needed. The occurrence and development of LUAD is a gradual multi-stage process involving multiple genes and steps (Dong et al, 2019). Most previous studies have focused on a single gene or pathway, and the connections between different pathways have not been explored sufficiently.…”