Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers.
In: Proceedings of the National Academy of Sciences of the United States of America, Jg. 115 (2018-10-02), Heft 40, S. 10094-10099
Online
academicJournal
Zugriff:
Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of Pten , p53 , and Smad4 , CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of CRPC.
Competing Interests: The authors declare no conflict of interest.
Titel: |
Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers.
|
---|---|
Autor/in / Beteiligte Person: | Feng, S ; Cheng, X ; Zhang, L ; Lu, X ; Chaudhary, S ; Teng, R ; Frederickson, C ; Champion, MM ; Zhao, R ; Cheng, L ; Gong, Y ; Deng, H |
Link: | |
Zeitschrift: | Proceedings of the National Academy of Sciences of the United States of America, Jg. 115 (2018-10-02), Heft 40, S. 10094-10099 |
Veröffentlichung: | Washington, DC : National Academy of Sciences, 2018 |
Medientyp: | academicJournal |
ISSN: | 1091-6490 (electronic) |
DOI: | 10.1073/pnas.1800695115 |
Schlagwort: |
|
Sonstiges: |
|