Tumor microenvironment macrophage inhibitory factor directs the accumulation of interleukin-17-producing tumor-infiltrating lymphocytes and predicts favorable survival in nasopharyngeal carcinoma patients.
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.
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: lijiang2@mail.sysu.edu.cn.
Jiang
J
Li
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Hao-Yuan
HY
Mo
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Geng
G
Xiong
Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Lin
L
Zhang
Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Jia
J
He
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Zhou-Feng
ZF
Huang
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Zhi-Wei
ZW
Liu
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Qiu-Yan
QY
Chen
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Zi-Ming
ZM
Du
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Li-Min
LM
Zheng
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503. Electronic address: qianchn@sysucc.org.cn.
Chao-Nan
CN
Qian
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Yi-Xin
YX
Zeng
D000328:Adult; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D009303:Nasopharyngeal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000276:immunology; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D015996:Survival Rate; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques; D059016:Tumor Microenvironment
C527276:CXCR4 protein, human; D016207:Cytokines; D020381:Interleukin-17; D008263:Macrophage Migration-Inhibitory Factors; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human