Distribution and prognostic value of macrophages in colorectal cancer and adjacent mucosa in patient stages I-III vs IV

BACKGROUND Synchronous and metachronous liver metastases (LM) of colorectal cancer (CRC) drastically worsen the patient’s survival. The biological and immunological mechanisms underlying these distinct metastatic trajectories remain incompletely understood. Prognostic impact of macrophages in primary CRC (pCRC) is uncertain, with discrepant findings reported for different macrophage subsets and different stage of the disease. Most of prior studies of tumor-infiltrating macrophages in CRC have focused primarily on the tumor core or invasive margin, whereas less attention has been given to the adjacent nontumor mucosa (NM), which may harbor early immunological alterations that precede or accompany metastatic spread. AIM To evaluate distribution and prognostic value of macrophages in pCRC and NM in patients at stage I-III vs IV. METHODS Paired specimens of pCRC and NM were collected retrospectively from: (1) Stage IV (n = 55) patients with synchronous LM; and (2) Stage I-III (n = 44) patients who developed metachronous LM thereafter. After immunohistochemical staining CD68+ (M0), CD80+ (M1), CD206+ and CD163+ (M2) macrophages were quantified in NM and tumor center (TC) of pCRC. Cell densities in NM and TC and TC/NM ratios were tested as prognostic variables for overall survival since liver surgery. Cox-regression and Kaplan-Meier analyses were applied using the R environment. RESULTS Densities of macrophages followed the declining pattern from CD163+ through CD206+ and CD68+ to CD80+ in both NM and TC, with significantly smaller densities of all cell types in tumors. Greater densities of CD80+ cells were observed in NM in stage I-III over stage IV patients: 309 (24-1143) cells/mm2 vs 208 (3-1084) cells/mm2 [median (minimum-maximum), P = 0.04]. High CD163+ cell density in NM in stage IV [hazard ratio = 0.45 (95%CI: 0.22-0.95), P = 0.04] and CD80+ cell density in NM in stage I-III [hazard ratio = 0.24 (95%CI: 0.10-0.57), P = 0.001] were associated with longer overall survival. CONCLUSION Contrary to TC of pCRC, we found favorable prognostic implications of macrophages in NM, driven by distinct subsets of macrophages in stage IV (CD163+ M2) and stage I-III CRC (CD80+ M1).