Foxp3+/ <scp>CD4</scp> + Cell Ratio in Primary Colorectal Cancer Predicts Opposite Prognoses Following Resection of Synchronous or Metachronous Liver Metastases

BACKGROUND: We aimed to assess the abundance, distribution, and prognostic significance of Foxp3+ and CD4+ T-cells and their ratio in primary colorectal cancer (pCRC) and liver metastases (LM) in patients with synchronous and metachronous disease. METHODS: We performed a retrospective study involving patients who underwent resections of both pCRC and either synchronous (N = 55) or metachronous LM (N = 44). Following sequential immunohistochemical staining for CD4+ and Foxp3+ T-cells, whole-slide scans were analyzed using QuPath software to quantify T-cells in the tumor center (TC), inner margin (IM), outer margin (OM), and peritumor zone (PT) of both pCRC and LM. T-cell densities and their ratios were tested as prognostic variables for disease-free survival (DFS) and time to recurrence (TTR). RESULTS: We found greater densities of CD4+ cells in OM and PT of LM of synchronous and metachronous patients compared to pCRC. In both groups, densities of Foxp3+ cells were higher in all regions of interest of pCRC compared to LM. CD4+ cells were more abundant than Foxp3+ cells in IM, OM, and PT of LM; densities of Foxp3+ cells were higher in TC and IM of pCRC. Neither CD4+ nor Foxp3+ cells in pCRC were individually predictive of survival, but a higher Foxp3+/CD4+ cells ratio in OM of pCRC in the metachronous group was associated with shorter DFS (hazard ratio (HR): 2.34, 95% confidence interval (CI): 1.14-4.79, p = 0.02) and TTR. Conversely, in OM and PT of pCRC in the synchronous group, a higher ratio was associated with longer DFS (HR: 0.53, CI: 0.29-0.98, p = 0.04 and HR: 0.46, CI: 0.25-0.86, p = 0.02, respectively) and TTR. CONCLUSIONS: The high Foxp3+/CD4+ cells ratio was associated with shorter survival in metachronous and longer survival in synchronous disease, providing novel clinical implications. Foxp3+/CD4+ cells ratio in pCRC may help better stratify CRC patients with synchronous LM after resection of the primary tumor.