Tumor-Associated Macrophage Infiltration in Colorectal Cancer Liver Metastases is Associated With Better Outcome.

Abstract

Tumor-associated macrophages (TAMs) support growth in most human cancers, with the notable exception of colorectal adenocarcinoma, in which TAM infiltration of primary tumors is correlated with a better outcome. The importance of TAMs in colorectal liver metastases (CLM) is unknown. Using a tissue microarray of CLM resected at their institution from 1998 to 2000, the authors quantified immune marker expression by immunohistochemistry (IHC) using Metamorph Image Analysis software. Findings showed that CD68, CD3, CD4, CD8, FoxP3, and MHC-I were correlated with overall survival (OS) and disease-free survival (DFS). Tumor cores from 158 patients were analyzed. The median follow-up period was 117months for survivors (n=39). The univariate analysis showed a significant positive association between DFS and CD4+ (p=0.025) and CD68+ (p=0.007). The findings showed a significant positive correlation of OS with CD4+ (p=0.042), whereas the correlation with CD68+ was not significant (p=0.17). Cutoffs were determined to dichotimize each marker for the highest log-rank statistic. Patients with CD4high had a median OS of 115months and DFS of 41months (p=0.007 compared with 40 and 16months, respectively, for patients with CD4low (p=0.022). Patients with CD68high had a median OS of 50months and a median DFS of 25months (p=0.67) compared with 43 and 15months (p=0.028). In the multivariate analysis of factors affecting DFS, high CD68 was associated with longer DFS (hazard ratio [HR], 0.63, 95% confidence interval [CI], 0.43-0.94; p=0.02), independently of clinicopathologic variables and CD4. High TAM infiltration in resected CLM is associated with better outcome, independently of known clinicopathologic and immune predictors. This suggests that TAM depletion, which is being tested clinically in other cancers, may be detrimental in CLM.