New Study Identifies Novel Mechanism for Tumor Immune Tolerance
Source:
Time: 2012-09-14
Immune-escaped tumor cells can evade T cell recognition or even actively inhibit antitumor T cell function and then develop to clinically apparent cancer. Whether and how T cells respond to tumor growth remain largely unknown. Now researchers from Chinese Academy of Sciences found that T cells respond to tumor growth through persistently elevating c-Fos expression, which eventually causes inhibition of antitumor T cell function.
Researchers led by Prof. LIU Xiaolong from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences found that c-Fos in T cells was up-regulated during tumor growth and accompanied by T cell activation. However, by introducing tumor growth into T cell c-Fos -overexpressed or -depleted mouse models, the researchers observed unexpected immune inhibitive role of c-Fos. Follow-up studies identified a new binding site through which c-Fos/AP-1 directly activate PD-1 expression. Induced immune inhibitory receptor PD-1 then down-regulated T cell function in PD-1 ligand-rich tumor microenvironment. Importantly, the AP-1 binding site mutant mice exhibited abrogated PD-1 induction, enhanced antitumor T cell function and reduced tumor growth.
This study provides new insight into T cell response during tumor growth, and also offers opportunities for drug development for treatment of cancer and chronic infection. This work was published in Proceedings of the National Academy of Science of the United States of America and was supported by grants from Ministry of Science and Technology, National Natural Science Foundation of China and Shanghai Municipal Government.
This study provides new insight into T cell response during tumor growth, and also offers opportunities for drug development for treatment of cancer and chronic infection. This work was published in the Proceedings of the National Academy of Science of the United States of America and was supported by grants from Ministry of Science and Technology, National Natural Science Foundation of China and Shanghai Municipal Government.
CONTACT:
Dr. LIU Xiaolong
Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
Mutation of the AP-1 binding site relieves spontaneous tumor growth and enhanced T cell anti-tumor function in Pdcd1KI/KI PyMT mice. (A) Reduced PD-1 expression in CD44hi tumor-infiltrating T cells from Pdcd1KI/KI PyMT mice at day 130 after birth. (B) Tumor onset was delayed in Pdcd1KI/KI PyMT mice. (C) Mouse mammary tumor growth was decelerated in Pdcd1KI/KI PyMT mice. (D) Reduced tumor growth showed by sections with HE staining at day 130 after birth. (E) Cleaved caspase-3 staining of tumor sections from (D) showed increased tumor cell apoptosis in Pdcd1KI/KI PyMT mice. (Image provided by Dr. LIU Xiaolong)
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