Spatial comparison and prognostic significance of macrophages in matched primary colorectal cancer and liver metastases: a retrospective study

Abstract

Analyzing the spatial distribution and prognostic significance of tumor-associated macrophages (TAMs) in primary colorectal cancer (pCRC) and matched liver metastases (LM) may provide insights into the immunological mechanisms behind malignancy and inform therapeutic strategies. Specimens of pCRC and LM were retrospectively collected from patients who underwent curative resection of both tumors, including those with synchronous LM (n = 55) and metachronous LM (n = 44). Immunohistochemical staining was applied and then pan-macrophages (CD68+), M1 (CD80+), and M2 (CD163+ and CD206+) TAMs were quantified across different regions of interest (ROI) within both pCRC and LM. TAM densities and their ratios were assessed in relation to overall survival (OS) in both groups and to time to liver metastasis (TLM) in metachronous group. In both the synchronous and metachronous groups, CD163+ cells showed the highest densities, whereas CD80+ cells were consistently the least abundant across all ROI. Outer margin (OM) and peritumoral zone (PT) of LM exhibited higher CD163+ and lower CD80+ cell densities compared with the corresponding regions in pCRC (all P < 0.05). CD163+ TAMs also displayed higher densities than CD206+ TAMs across all ROI in both groups (all P < 0.001). In the metachronous group, high CD80+ density in the OM of pCRC correlated with longer OS but shorter TLM. In the synchronous group, a high CD80/CD206 ratio in the PT of pCRC was associated with shorter OS, whereas a high CD80/CD163 ratio in the corresponding region of LM predicted improved survival. Our findings demonstrate a strong polarization of TAMs toward the M2 phenotype across both synchronous and metachronous groups and in both pCRC and LM, with this shift being more pronounced in LM. High densities of CD80+ M1 macrophages in OM of pCRC of the metachronous group were associated with longer OS but shorter TLM, indicating their dual prognostic role. The results related to M1/M2 ratios further emphasize that the prognostic relevance of TAMs depends critically on the balance between macrophage subsets. Importantly, this balance varies according to whether M2 macrophages are defined by CD163 or CD206 expression and whether macrophages are assessed in the primary tumor or within the metastatic liver microenvironment.