Antigen presentation by dendritic cells in tumors is disrupted by altered metabolism that involves pyruvate kinase M2 and its interaction with SOCS3.
Dendritic cell (DC) function is negatively affected by tumors and tumor-derived factors, but little is known about the underlying mechanisms. Here, we show that intracellular SOCS3 in DCs binds to pyruvate kinase type M2 (M2-PK), which plays a critical role in ATP production through glycolysis. The interaction of SOCS3 with M2-PK reduced ATP production and impaired DC-based immunotherapy against tumors. Thus, SOCS3, which has been shown to be upregulated by tumor-derived factors, interacts with M2-PK to decrease ATP production, causing DC dysfunction. These dysfunctional DCs have a reduced ability to present antigens. Alteration of DC metabolism mediated by SOCS3 represents a novel mechanism for DC dysfunction in the tumor microenvironment.
Zhang
Zhuohan
Z
Department of Immunology, Nankai University School of Medicine and Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, People's Republic of China.
Liu
Qiaofei
Q
Che
Yongzhe
Y
Yuan
Xin
X
Dai
Lingyun
L
Zeng
Bin
B
Jiao
Guohui
G
Zhang
Yin
Y
Wu
Xue
X
Yu
Yinyan
Y
Zhang
Yuan
Y
Yang
Rongcun
R
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D015153:Blotting, Western; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D047468:Immunoprecipitation; D007167:Immunotherapy; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D011770:Pyruvate Kinase / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology / Q000378:metabolism*; D013552:Swine
C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000255:Adenosine Triphosphate; D011770:Pyruvate Kinase