12-Chemokine signature, a predictor of tumor recurrence in colorectal cancer

Abstract

Tertiary lymphoid structures (TLSs) provide an immunological antineoplastic effect. Recent evidences link a unique 12-chemokine (CCL2, -3, -4, -5, -8, -18, -19, -21, CXCL9, -10, -11, -13) signature status from tumor tissue and the TLS expression. However, the potential significance of 12-chemokine signature status for clinical use is unknown. We aimed to evaluate the association of 12-chemokine signature status with patient outcomes in colorectal cancer (CRC). We used integrated data of resected 975 CRC cases within three independent cohorts from France, Japan and the United States (GSE39582, KUMAMOTO from Kumamoto university hospital and TCGA). The association of 12-chemokine signature status with clinicopathological features, patient outcome, TLS expression status and key tumor molecular features was analyzed. Patients with low 12-chemokine signature status had a significant shorter relapse-free survival in discovery cohort (HR: 1.61, 95% CI: 1.11-2.39, p = 0.0123), which was confirmed in validation cohort (HR: 3.31, 95% CI: 1.33-10.08, p = 0.0087). High 12-chemokine signature status had significant associations with right-sided tumor, high tumor-localized TLS expression, BRAF mutant, CIMP-high status and MSI-high status. Furthermore, RNA-seq based analysis showed that high 12-chemokine signature status was strongly associated with inflammation-related, immune cells-related and apoptosis pathways (using gene set enrichment analysis), and more tumor-infiltrating immune cells, such as cytotoxic T lymphocytes and myeloid dendritic cells (using MCP-counter analysis). We investigated a promising effect of 12-chemokine signature status in CRC patients who underwent resection. Our data may be helpful in developing novel immunological treatment strategies for CRC.

Keywords: 12-chemkine signature; TLS; colorectal cancer; recurrence; tumor infiltrating immune cells.

Figure 1.

Flow chart showing the inclusion/exclusion criteria in our study using three independent cohorts.

Figure 2.

The associations of 12-chemokine signature status with patient outcome, TLS expression and tumor molecular features. (a) 12-chemokine gene enrichment analysis. (b, c) The probabilities (Kaplan–Meier plots) and hazard ratios (spline plots) for overall (b) and relapse-free (c) survival by 12-chemokine signature status. (d, e) 12-chemokine signature status and TLS expression status for peritumoral reaction (d) or Crohn’s-like reaction (e). (f) 12-chemokine signature status and tumor molecular features. Abbreviations: CIMP, CpG island methylator phenotype; MSI, microsatellite instability; MSS, microsatellite stable; TLS, tertiary lymphoid structure.

Figure 3.

Gene set enrichment analysis and the association between 12-chemokine signature status and tumor-infiltrating immune and stromal cells. (a) Gene set enrichment analysis with hallmarks gene sets in the GSE 39582 and TCGA cohort (high 12-chemokine signature status vs. low 12-chemokine signature status). (b) The association between 12-chemokine signature status and tumor-infiltrating immune and stromal cells. Abbreviations: CTLs, cytotoxic T lymphocytes; myeloid DCs, myeloid dendritic cells; NK cells, natural killer cells.