Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers

Shan Feng, Xi Cheng, Lin Zhang, Xuemin Lu, Seema Chaudhary, Ruifang Teng, Christian Frederickson, Matthew M. Champion, Ren Zhao, Liang Cheng, Yiyi Gong, Haiteng Deng, Xin Lu

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)10094-10099
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number40
DOIs
StatePublished - Oct 2 2018

Fingerprint

Prostatic Neoplasms
Castration
T-Lymphocytes
Reactive Nitrogen Species
Neoplasms
Protein-Tyrosine Kinases
Interleukin-2
Proteins
Lymphocytes
Critical Pathways
Tumor Microenvironment
Reducing Agents
Immunosuppressive Agents
T-Cell Antigen Receptor
Nitrates
Transgenic Mice
Tyrosine
Myeloid-Derived Suppressor Cells
Lung Neoplasms
Cell Death

Keywords

  • Immune checkpoint blockade
  • LCK
  • Myeloid-derived suppressor cells
  • Prostate cancer
  • Protein nitration

ASJC Scopus subject areas

  • General

Cite this

Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers. / Feng, Shan; Cheng, Xi; Zhang, Lin; Lu, Xuemin; Chaudhary, Seema; Teng, Ruifang; Frederickson, Christian; Champion, Matthew M.; Zhao, Ren; Cheng, Liang; Gong, Yiyi; Deng, Haiteng; Lu, Xin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 40, 02.10.2018, p. 10094-10099.

Research output: Contribution to journalArticle

Feng, S, Cheng, X, Zhang, L, Lu, X, Chaudhary, S, Teng, R, Frederickson, C, Champion, MM, Zhao, R, Cheng, L, Gong, Y, Deng, H & Lu, X 2018, 'Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 40, pp. 10094-10099. https://doi.org/10.1073/pnas.1800695115
Feng, Shan ; Cheng, Xi ; Zhang, Lin ; Lu, Xuemin ; Chaudhary, Seema ; Teng, Ruifang ; Frederickson, Christian ; Champion, Matthew M. ; Zhao, Ren ; Cheng, Liang ; Gong, Yiyi ; Deng, Haiteng ; Lu, Xin. / 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. 2018 ; Vol. 115, No. 40. pp. 10094-10099.
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AU - Teng, Ruifang

AU - Frederickson, Christian

AU - Champion, Matthew M.

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AU - Deng, Haiteng

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AB - 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.

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