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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-10, Vol.115 (40), p.10094-10099
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Apoptosis; Biological Sciences; Cancer therapies; Carcinoma, Lewis Lung - genetics; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - pathology; Castration; Cell activation; Cell death; Cell proliferation; Clonal deletion; CTLA-4 protein; Deactivation; Humans; Immune checkpoint; Immunoglobulins; Immunological tolerance; Immunosuppression; Inactivation; Interleukin 2; Jurkat Cells; Lck protein; Lung cancer; Lymphocyte Activation; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - immunology; Lymphocytes; Lymphocytes T; Male; Mice; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - pathology; Nitrates; Nitration; Nitrotyrosine; Organic chemistry; p53 Protein; PD-1 protein; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - immunology; Prostatic Neoplasms, Castration-Resistant - pathology; Protein-tyrosine kinase; Proteins; PTEN protein; Reactive nitrogen species; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Reducing agents; Rodents; Smad4 protein; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Therapy; Transgenic mice; Tyrosine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1800695115

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.