Abstract
The accumulation of an intratumoral CD4(+) interleukin-17-producing subset (Th17) of tumor-infiltrating lymphocytes (TILs) is a general characteristic in many cancers. The relationship between the percentage of Th17 cells and clinical prognosis differs among cancers. The mechanism responsible for the increasing percentage of such cells in NPC is still unknown, as is their biological function. Here, our data showed an increase of Th17 cells in tumor tissues relative to their numbers in normal nasopharynx tissues or in the matched peripheral blood of NPC patients. Th17 cells in tumor tissue produced more IFNγ than did those in the peripheral blood of matched NPC patients and healthy controls. We observed high levels of CD154, G-CSF, CXCL1, IL-6, IL-8, and macrophage inhibitory factor (MIF) out of 36 cytokines examined in tumor tissue cultures. MIF promoted the generation and recruitment of Th17 cells mediated by NPC tumor cells in vitro; this promoting effect was mainly dependent on the mammalian target of rapamycin pathway and was mediated by the MIF-CXCR4 axis. Finally, the expression level of MIF in tumor cells and in TILs was positively correlated in NPC tumor tissues, and the frequency of MIF-positive TILs was positively correlated with NPC patient clinical outcomes. Taken together, our findings illustrate that tumor-derived MIF can affect patient prognosis, which might be related to the increase of Th17 cells in the NPC tumor microenvironment.
Highlights
Tumor microenvironments affect the progression of cancers
We have shown for the first time that microenvironment-derived macrophage inhibitory factor (MIF) promoted the generation and migration of Th17 cells mediated by tumor cells, and the promotion effect of MIF on the generation and recruitment of Th17 cells was mainly dependent on the mTOR pathway and was mediated by the MIF-CXCR4 axis
Th17 Cells Were Enriched in Tumor-infiltrating Lymphocytes— An increase of Th17 cells in the tumor microenvironment is becoming recognized as a general characteristic of cancers [11, 21, 22]
Summary
Results: We demonstrated that Th17 cells were accumulated in tumor tissues, and the tumor-derived MIF induced Th17 cell accumulation and had clinical relevance in NPC. Significance: The tumor microenvironment influences the clinical prognosis of NPC patients. Our data showed an increase of Th17 cells in tumor tissues relative to their numbers in normal nasopharynx tissues or in the matched peripheral blood of NPC patients. Th17 cells in tumor tissue produced more IFN␥ than did those in the peripheral blood of matched NPC patients and healthy controls. MIF promoted the generation and recruitment of Th17 cells mediated by NPC tumor cells in vitro; this promoting effect was mainly dependent on the mammalian target of rapamycin pathway and was mediated by the MIF-CXCR4 axis. The expression level of MIF in tumor cells and in TILs was positively correlated in NPC tumor tissues, and the frequency of MIF-positive TILs was positively correlated with NPC patient clinical outcomes
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