Tumor-associated macrophages and risk of recurrence in stage III colorectal cancer

Abstract

Tumor-associated macrophages (TAMs) have a unique favorable effect on the prognosis of colorectal cancer (CRC), although their association with stage-specific outcomes remains unclear. We assessed the densities of CD68⁺ and CD163⁺ TAMs at the invasive front of resected CRC stage III CRC from 236 patients, 165 of whom received post-surgical FOLFOX treatment, and their relationship with disease-free survival (DFS). Associations between macrophage mRNAs and clinical outcome were investigated in silico in 59 stage III CRC and FOLFOX-treated patients from The Cancer Genome Atlas (TCGA). Biological interactions of SW480 and HT29 cells and macrophages with FOLFOX were tested in co-culture models. Low TAM densities were associated with shorter DFS among patients receiving FOLFOX (CD68⁺ , p = 0.0001; CD163⁺ , p = 0.0008) but not among those who were untreated. By multivariate Cox analysis, only low TAM (CD68⁺ , p = 0.001; CD163⁺ , p = 0.002) and nodal status (CD68⁺ , p = 0.009; CD163⁺ , p = 0.007) maintained an independent predictive value. In the TCGA cohort, high CD68 mRNA levels were associated with better outcome (p = 0.02). Macrophages enhanced FOLFOX cytotoxicity on CRC cells (p < 0.01), and drugs oriented macrophage polarization from M2- to M1-phenotype. Low TAM densities identify stage III CRC patients at higher risk of recurrence after adjuvant therapy, and macrophages can augment the chemo-sensitivity of micro-metastases.

Keywords: adjuvant therapy; cancer immunology; colorectal cancer; macrophage polarization; tumor-associated macrophages.