{'fraction_non_alphanumeric': 0.02829121086382497, 'fraction_numerical': 0.006035458317615994, 'mean_word_length': 5.597014925373134, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers

Significance Immune checkpoint blockade (ICB) to reinvigorate cytotoxic T lymphocytes using antibodies against CTLA4 or PD1 generates durable therapeutic responses in patients across a variety of cancer types. However, some cancers such as castration-resistant prostate cancer (CRPC) show overwhelming resistance to ICB. Here, we develop a nitroproteomic approach and uncover a potential mechanism for the immunotherapy resistance where a key protein for T cell activation, lymphocyte-specific protein tyrosine kinase (LCK), is nitrated and inactivated by myeloid-derived suppressor cell–generated reactive nitrogen species (RNS) in the resistant tumor. An agent that neutralizes RNS significantly sensitizes CRPC to ICB therapy in a mouse model. Therefore, our studies illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of ICB-resistant cancers. 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.