JAK1 expression in multiple human tumours
We evaluated the differences in JAK1 expression in various human tumour tissues and paired normal tissues using RNA sequencing data from the TCGA. The detailed expression of JAK1 in the tumour and adjacent tissues is shown in Fig. 1A. JAK1 expression was significantly decreased in BLCA (bladder urothelial carcinoma), BRCA (breast invasive carcinoma), COAD (colon adenocarcinoma), KICH (kidney chromophobe), LUAD, LUSC, PRAD (prostate adenocarcinoma), READ (rectum adenocarcinoma), and UCEC (uterine corpus endometrial carcinoma) compared to that in adjacent normal tissues, while the expression of JAK1 was significantly higher in CHOL (cholangiocarcinoma), ESCA (oesophageal carcinoma), HNSC (head and neck squamous cell carcinoma), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma), LIHC (liver hepatocellular carcinoma), STAD (stomach adenocarcinoma), and THCA (thyroid carcinoma) than that in adjacent normal tissues.
To further evaluate the expression patterns of JAK1 in NSCLC, the GEPIA database was further selected. Similar results were likewise obtained, namely, JAK1 expression in LUAD and LUSC was significantly lower than that in the paired normal tissues (Fig. 1B).
JAK1 expression predicts the prognosis of NSCLC
Next, we explored the prognostic value of JAK1 for NSCLC by adopting two public databases. First, we investigated JAK1 expression and the prognosis of NSCLC, LUAD and LUSC using Kaplan–Meier Plotter, which principally focused on the strength of the information from the GEO, EGA and TCGA miRNA gene chips. The results showed that high JAK1 expression indicated a favourable prognosis in NSCLC (OS: HR, 0.62, 95% CI from 0.53 to 0.74, log-rank P < 0.001; PFS: HR, 0.65, 95% CI from 0.50 to 0.86, log-rank P = 0.002). In the subgroup analysis, the high expression of JAK1 in LUAD lasted longer in OS (HR: 0.74, 95% CI from 0.58 to 0.95, log-rank P = 0.017), but there was no benefit in PFS (HR: 0.83, 95% CI from 0.60 to 1.14, log-rank P = 0.24). In LUSC, high expression of JAK1 was associated with longer duration of PFS (HR: 0.65, 95% CI from 0.39 to 1.09, log-rank P = 0.097), while the difference was not statistically significant. In addition, there was no benefit in OS (HR: 0.95, 95% CI from 0.69 to 1.29, log-rank P = 0.73). (Fig. 2).
Next, we investigated the association of JAK1 expression and prognosis with distinct clinicopathological features in NSCLC (Table 1). JAK1 overexpression related to superior OS and PFS in males (HR: 0.64, 0.62, 95% CI from 0.52 to 0.79, P < 0.001) rather than females. In addition, the higher expression of JAK1 is associated with preferable OS in patients with N2 lymph node metastasis (HR: 0.39, 95% CI from 0.17 to 0.86, P = 0.016) without distant metastasis (HR: 0.73, 95% CI from 0.56 to 0.93, P = 0.013) of NSCLC. Notably, overexpression of JAK1 is associated with undesirable prognosis in patients with stage 1 NSCLC (OS: HR, 1.46, 95% CI from 1.06 to 2.00, P = 0.02) and without lymph node metastasis (PFS: HR, 2.18, 95% CI from 1.06 to 4.46, P = 0.029), which implicit early NSCLC patients with JAK1 overexpression may have a poor prognosis. Regrettably, there were no statistically significant differences between JAK1 expression and prognosis in females, stage 2 to 3, stage T1 to T4, N1 lymph node metastasis or prior chemotherapy. The exact survival time is shown in Additional file 1: Table S1.
Finally, we selected the PrognoScan database to further verify the relationship between JAK1 expression and prognosis in NSCLC. Five cohorts containing a total of 530 patients with NSCLC and LUAD showed that high expression of JAK1 was associated with favourable OS (Table 2).
Correlation of JAK1 expression and immune infiltration
Tumour infiltrating lymphocytes (TILs) are closely related to prognosis and subsequent immunotherapy in lung cancer [23, 24]. We investigated the correlation between JAK1 expression level and immune cell infiltration in LUAD and LUSC from TIMER. The results showed that JAK1 expression was negatively correlated with tumour purity (r = − 0.229, P = 2.73e-07) and significantly positively correlated with infiltrating levels of B cells (r = 0.155, P = 6.20e−04), CD8+ T cells (r = 0.307, P = 4.41e−12), CD4+ T cells (r = 0.422, P = 2.42e−22), macrophages (r = 0.342, P = 9.91e−15), neutrophils (r = 0.459, P = 1.41e−26), and dendritic cells (r = 0.479, P = 2.25e−29). Similar results were also observed in LUSC. JAK1 expression was negatively correlated with tumour purity (r = − 0.309, P = 5.34e−12) and significantly positively correlated with infiltrating levels of B cells (r = 0.224, P = 8.82e−07), CD8+ T cells (r = 0.26, P = 9.26e−09), CD4+ T cells (r = 0.517, P = 7.50e−34), macrophages (r = 0.405, P = 2.92e−20), neutrophils (r = 0.522, P = 1.36e−34), and dendritic cells (r = 0.5, P = 2.20e−31) (Fig. 3).
In addition, the public database TISIDB also explored the correlation between the abundance of multiple immune cells and JAK1 expression in NSCLC. The enrichment of diversified immune cells, such as Act_CD4, Act_DCs, iDCs, neutrophils, NK cells, pDCs, Tcm_CD4 and Tem_CD8, was positively correlated with JAK1 expression in LUAD and LUSC. What needs illustration is that JAK1 expression has no significant corrections with infiltrating levels of Act_CD4 in LUSC. For details, please refer to Fig. 4 and Additional file 1: Fig S1.
Correlations between JAK1 expression and immune gene markers
To further understand the interaction between JAK1 expression and TME in NSCLC. We further explored the potential correlation between JAK1 and immune gene markers in the public databases TIMER and GEPIA (Tables 3, 4). These gene markers depicted diverse immune infiltration cells, including monocytes, TAMs, M1 macrophages, M2 macrophages, CD8+ T cells, B cells, neutrophils, dendritic cells and NK cells. In addition, various T cells, including Th1, Th2, Tregs, and T cell exhaustion, which play different functions in the TME, were included. Although they were adjusted for tumour purity, most immune markers remained significantly related to JAK1 expression levels in LUAD and LUSC.
Interestingly, the results from TIMER and GEPIA showed that most gene sets of monocytes, M1 macrophages, and TAMs were significantly associated with JAK1 expression levels in LUAD. However, we discovered that JAK1 expression was also associated with most gene sets of monocytes and TAMs rather than M1 macrophages. Notably, the majority chemokine ligand, which induced cells of the immune system to enter the site of infection, CCL-2, CD80 and CD68 of TAMs, IRF5 and NOS2 of M1, CD163 and MS4A4A of M2 were strongly related to JAK1 expression in LUAD (all P value < 0.0001). These consequences suggest that JAK1 may play a vital role in the TME by regulating the function of macrophages. In addition, some of the gene markers, such as MPO, CCR7 and CD11b (ITGAM), of neutrophils and CD8A of CD8+ T cells were associated with JAK1 expression in LUAD and LUSC.
Moreover, the vast majority of gene sets of dendritic cells, including HLA-DPB1, HLA-DQB1, HLA-DRA, HLA-DPA1, BDCA-1, BDCA-4 and CD11C, were positively correlated with JAK1 expression levels in LUAD and LUSC. These results indicated that LAYN may regulate DCs to play a major role in the TME. Regretfully, nearly all of the gene markers of NK cells had no correlation with JAK1 expression levels. Furthermore, we investigated the relationship between JAK1 expression and gene sets of Tregs and T cell exhaustion. All gene sets suggested a positive correlation with JAK1 expression. Finally, immune checkpoints such as PD-1, CTLA4, LAG3 and TIM3 were strongly connected with the level of JAK1 expression, which suggested that JAK1 may play a role in immunotherapy for NSCLC. Further molecular biology experiment verification is needed.
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