Tumor-infiltrating lymphocyte signature in epithelial and stromal compartments of an esophageal squamous cell carcinoma acidic microenvironment mediated by MCT4

Tumor-infiltrating lymphocytes (TILs), including but not limited to neutrophils, M2 macrophages, cytotoxic CD8 T cells and dendritic cells, will play a role in the acidic tumor microenvironment mediated by monocarboxylate transporter 4 (MCT4) in esophageal squamous cell carcinoma (ESCC). However, the roles they play and their significance in ESCC remain less clear. To understand the clinicopathological and prognostic significance of neutrophils, M2 macrophages, CD8 T cells and dendritic cells in the tumor acidic microenvironment mediated by MCT4, we investigated the distribution of these TILs in the epithelial and stromal compartments of ESCC by means of multiplexed immunohistochemistry on a tissue microarray containing 87 paired dots of ESCC and its adjacent normal tissue (ANT) and an additional 6 cases of unpaired ESCC dots. The density of cells stained with MCT4 in the epithelium was significantly associated with overall survival. Dendritic cells stained with S100 in epithelial compartmentalization were found to markedly correlate with clinical stage and tumor invasion depth. No other significant association could be identified in terms of prognostic and clinicopathological significance. The potential correlation between the number of cells stained with MCT4 versus the number of TILs was also explored, showing that only in epithelial cells were there significant and positive correlations identified between the number of cells stained with MCT4 versus the number of neutrophils stained with CD15, M2 macrophages stained with CD163 and CD8 T cells stained by CD8a. However, no significant correlation was found along the stromal line. Together, the data we described here, although somewhat discouraging, showed that in epithelial cells from which ESCC originated, acidicity mediated by MCT4 may be responsible for lactate release and may have an effect on the infiltration of TILs we assessed.

Automated summary

This study investigated the distribution and significance of tumor-infiltrating lymphocytes in the acidic tumor microenvironment of esophageal squamous cell carcinoma (ESCC). The findings showed that the density of cells stained with MCT4 in the epithelium was significantly associated with overall survival. Dendritic cells stained with S100 in the epithelial compartment correlated with clinical stage and tumor invasion depth.