Tumor-infiltrating Immune Cells In Digestive System Cancers: Clinical Significance And Mechanisms

Digestive system cancers, including gastric cancer, esophageal squamous cell carcinoma(ESCC), colorectal carcinoma and hepatocellular carcinoma (HCC), are the commonmalignancies throughout the world. These tumors usually arise at the sites of chronicinflammation with amounts of infiltrating immune cells. Monocytes/macrophages (Mo/M_φ)and mast cells are two critical mediators that could profoundly regulate the tumor progressionin human solid tumors. However, the clinical significance and related mechanisms of tumorinfiltrating Mo/M_φ and mast cells during digestive system cancers progression are less clear.The present study investigated the relationship between the type, density, and location ofMo/M_φ and mast cells within tumors and the clinical outcome of the patients as well as theunderlying mechanisms. The major findings are summarized as follows:1) Human solid tumor is the results of long term co-evolution between cancer cells andhost immune systems; and can be classified anatomically into areas of intratumor, invadingedge, peritumoral stroma and peritumor, each with distinct compositions and functionalproperties. Using CD68as a pan-Mo/M_φ marker, we found that high density of intratumoralMo/M_φ could predict better overall survival (OS) in patients with gastric cancer, whereasboth nontumoral and peritumoral Mo/M_φ density were not associated with OS. Moreover,there is no association between intratumoral Mo/M_φ density and OS in patients with ESCC.These results indicated that tumor associated Mo/M_φ might have distinct subpopulations andclinical impact in different types of human tumors and/or different micro-location of a tumor.2) CD169is a macrophage-restricted cellular interaction molecule and an importantmember of the Siglec family. In this study, we found that CD169is a specific signature ofMo/M_φ in human tumors, such as HCC, gastric cancer, ESCC and colorectal carcinoma. Thedensity of CD169~+Mo/M_φ decreased in both peritumor stroma and intratumor compared withperitumor in HCC tissues. However, CD169~+Mo/M_φ are accumulated in tumoral tissues of gastric cancer (intratumor) and colorectal carcinoma (tumor front). Although pan-Mo/M_φ(CD68~+Mo/M_φ) infiltration have conflicting prognosis significance in HCC, gastric cancerand colorectal carcinoma, the present study showed that high densities of CD169~+Mo/M_φ areassociated with good prognosis in tumoral tissues of all these tumors. Taken together, theseresults indicated that CD169might be a candidate marker for a functionally distinct Mo/M_φsubpopulation in human tumors.3) Proinflammatory cytokine interleukin17(IL-17) could facilitate the diseaseprogression in HCC, but exhibite anti-tumoral activities in ovarian cancer, prostate cancer andmelanoma. IL-17, mainly expressed by T lymphocytes (Th17), has been investigated inperipheral blood of patients in many types of cancer, but its expression and in situ distributionin tumoral tissue remain largely unknown. In this study, we identified that connective tissuemast cells (MCTC), but not T lymphocytes, are the main producers of IL-17in ESCC in situ.IL-17~+cells are predominantly located in the muscularis propria (MP) rather than in the tumornest (TN) of ESCC tissues. Survival analysis on215ESCC patients with long-term follow updata (>15years) showed that high density of IL-17~+MPcells is correlated to low depth oftumor invasion (pT) and increased survival. Moreover, we found that density of IL-17~+MPcells is positively associated with other effector cells in the same area (MP), such as CD68~+MPmacrophages, CD169~+MPmacrophages and CD8~+MPT cells. These results highlighted thatIL-17~+MPMCTCmay play anti-tumoral function in ESCC.Conclusion and Significance: The results are summarized as follows:1) IntratumoralCD68~+Mo/M_φ density is associated with good prognosis in gastric cancer, but not in ESCC.Different from the conflicting prognosis significance of pan-Mo/M_φ (CD68~+Mo/M_φ) inmany tumors, high intratumoral CD169~+Mo/M_φ density is a favorable sign in patients withHCC, gastric cancer and colorectal carcinoma, indicated that CD169may be a candidatemarker for a functionally distinct Mo/M_φ subpopulation in human tumors.2) Tumorinfiltrating MCTCis the major source of IL-17in ESCC in situ. The density of IL-17~+MPcellsis an independent prognostic factor for ESCC patients, and its accumulation is positivelycorrelated with other effector cells, which highlighted the anti-tumoral function of these cells.Taken together, these results suggested that tumor infiltrating immune cells could exhibitedistinct phenotype and function in different niches of tumors. Thus, studying the mechanismsthat can selectively modulate the phenotype and/or functional activities of Mo/M_φ and mastcell might provide a novel strategy for anticancer therapy.