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. 2021 Aug 23:11:711402.
doi: 10.3389/fonc.2021.711402. eCollection 2021.

Prognostic Biomarkers and Immunotherapeutic Targets Among CXC Chemokines in Pancreatic Adenocarcinoma

Jiacheng Huang  1   2   3 , Zhitao Chen  1   2 , Chenchen Ding  1 , Shengzhang Lin  1 , Dalong Wan  3 , Kuiwu Ren  3   4
Affiliations

Prognostic Biomarkers and Immunotherapeutic Targets Among CXC Chemokines in Pancreatic Adenocarcinoma

Jiacheng Huang et al. Front Oncol. .

Abstract

Background: Pancreatic cancer is one of the principal causes of tumor-related death worldwide. CXC chemokines, a subfamily of functional chemotactic peptides, affect the initiation of tumor cells and clinical outcomes in several human malignant tumors. However, the specific biological functions and clinical significance of CXC chemokines in pancreatic cancer have not been clarified.

Methods: Bioinformatics analysis tools and databases, including ONCOMINE, GEPIA2, the Human Protein Atlas, DAVID, GeneMANIA, cBioPortal, STRING, DGidb, MethSurv, TRRUST, SurvExpress, SurvivalMeth, and TIMER, were utilized to clarify the clinical significance and biological functions of CXC chemokine in pancreatic cancer.

Results: Except for CXCL11/12, the transcriptional levels of other CXC chemokines in PAAD tissues were significantly elevated, and the expression level of CXCL16 was the highest among these CXC chemokines. Our findings also suggested that all of the CXC chemokines were linked to tumor-immune dysfunction involving the abundance of immune cell infiltration, and the Cox proportional hazard model confirmed that dendritic and CXCL3/5/7/8/11/17 were significantly associated with the clinical outcome of PAAD patients. Furthermore, increasing expressions of CXCL5/9/10/11/17 were related to unfavorable overall survival (OS), and only CXCL17 was a prognostic factor for disease-free survival (DFS) in PAAD patients. The expression pattern and prognostic power of CXC chemokines were further validated in the independent GSE62452 dataset. For the prognostic value of single CpG of DNA methylation of CXC chemokines in patients with PAAD, we identified 3 CpGs of CXCL1, 2 CpGs of CXCL2, 2 CpGs of CXCL3, 3 CpGs of CXCL4, 10 CpGs of CXCL5, 1 CpG of CXCL6, 1 CpG of CXCL7, 3 CpGs of CXCL12, 3 CpGs of CXCL14, and 5 CpGs of CXCL17 that were significantly associated with prognosis in PAAD patients. Moreover, the prognostic value of CXC chemokine signature in PAAD was explored and tested in two independent cohort, and results indicated that the patients in the low-risk group had a better OS compared with the high-risk group. Survival analysis of the DNA methylation of CXC chemokine signature demonstrated that PAAD patients in the high-risk group had longer survival times.

Conclusions: These findings reveal the novel insights into CXC chemokine expression and their biological functions in the pancreatic cancers, which might serve as accurate prognostic biomarkers and suitable immunotherapeutic targets for patients with pancreatic cancer.

Keywords: CXC chemokines; bioinformatics; immunotherapeutic targets; pancreatic cancer; prognostic biomarkers.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The transcriptional levels of CXC chemokines in several human malignant tumors (ONCOMINE). Upregulated expression (red); downregulated expression (blue).
Figure 2
Figure 2
The transcriptional levels of diverse CXC chemokine family members in PAAD tissues and adjacent pancreatic tissues (GEPIA2). PAAD tissues (red); adjacent pancreatic tissues (blue). *p < 0.01 and |Log2FC| > 1.
Figure 3
Figure 3
The relative expression level of CXC chemokine family members in LUAD (GEPIA2).
Figure 4
Figure 4
The biological functions and survival analysis of mutated CXC chemokines (cBioportal). (A) Summary of alterations in different expressed CXC chemokines family in PAAD. (B) Genetic alterations in CXC chemokines in PAAD. (C) The miRNA expression heatmap of CXC chemokines. (D, E) Survival curves of PAAD patients in altered and unaltered groups of the CXC chemokines. (D) OS; (E) DFS.
Figure 5
Figure 5
(A) The co-expression of CXC chemokines with each other based on the Pearson’s correlation coefficient for PAAD samples (cBioportal). (B, C) PPI network and functional relationship of CXC chemokines (STRING, GeneMANIA).
Figure 6
Figure 6
The correlation between CXC chemokines and immune cell infiltration (B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells) in PAAD (TIMER). (A) CXCL1 (B) CXCL2 (C) CXCL3 (D) CXCL4 (E) CXCL5 (F) CXCL6 (G) CXCL7 (H) CXCL8 (I) CXCL9 (J) CXCL10 (K) CXCL11 (L) CXCL12 (M) CXCL13 (N) CXCL14 (P) CXCL16 (O) CXCL17.
Figure 7
Figure 7
The correlation between each CXC chemokine expression and clinicopathological stages in patients with PAAD (GEPIA2).
Figure 8
Figure 8
The OS of single CXC chemokine in patients with PAAD (GEPIA2).
Figure 9
Figure 9
The DFS of single CXC chemokine in patients with PAAD (GEPIA2).
Figure 10
Figure 10
The heatmap of DNA methylation level of single CXC chemokine (MethSurv). High expression (red); low expression (blue).
Figure 11
Figure 11
The expressions levels and prognostic values of CXC chemokine signature in the training cohort (SurvExpress). (A) The heatmap of CXC chemokines in PAAD patients in the high- and low-risk group. (B) The expression levels of CXC chemokines between high- and low-risk groups. (C) Kaplan–Meier curves for survival analysis of CXC chemokines between high- and low-risk groups. (D) The survival ROC curves for survival prediction by the CXC chemokines assessed the accuracy of the prognostic model.
Figure 12
Figure 12
The expression levels and prognostic values of the DNA methylation of CXC chemokine signature in patients with PAAD (SurvivalMeth). (A) The DNA methylation level of single CXC chemokine in PAAD patients. (B) The heatmap of DNA methylation of CXC chemokines in PAAD patients in high- and low-risk groups. (C) The expression levels of DNA methylation of CXC chemokines between high- and low-risk groups. *p < 0.05; **p < 0.01. (D) Kaplan–Meier curves for survival analysis of DNA methylation of CXC chemokines between high- and low-risk groups.
Figure 13
Figure 13
External validation of the expression levels of CXC chemokines in independent GSE62452 cohort (GEO database). (A) CXCL1 (B) CXCL2 (C) CXCL3 (D) CXCL4 (E) CXCL5 (F) CXCL6 (G) CXCL7 (H) CXCL8 (I) CXCL9 (J) CXCL10 (K) CXCL11 (L) CXCL12 (M) CXCL13 (N) CXCL14 (O) CXCL16 (P) CXCL17.
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