Having previously demonstrated that MDSCs in tumors can suppress T cell activity via reactive nitrogen species (RNS), Feng and Cheng et al. utilized chemical derivation and LC-MS/MS to identify nitration of tyrosine (Tyr394) at LCK (an initiating tyrosine kinase in the TCR activation pathway) as the underlying mechanism for RNS-induced TIL suppression. In mouse models of castration-resistant prostate cancer and lung cancer, combining immune checkpoint blockade (anti-PD-1 + anti-CTLA-4) with RNS-neutralizing uric acid synergistically increased CD8+ T cell infiltration into the tumor and reduced tumor growth.
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.
Author Info: (1) Department of Biological Sciences, University of Notre Dame, Notre Dame, IN Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46
Author Info: (1) Department of Biological Sciences, University of Notre Dame, Notre Dame, IN Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. Ministry of Education Key Laboratory of Bioinformatics, School of Life Sciences and Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, 100084 Beijing, China. (2) Department of Biological Sciences, University of Notre Dame, Notre Dame, IN Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (3) Ministry of Education Key Laboratory of Bioinformatics, School of Life Sciences and Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, 100084 Beijing, China. (4) Department of Biological Sciences, University of Notre Dame, Notre Dame, IN Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (5) Department of Biological Sciences, University of Notre Dame, Notre Dame, IN Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (6) Ministry of Education Key Laboratory of Bioinformatics, School of Life Sciences and Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, 100084 Beijing, China. (7) Department of Biological Sciences, University of Notre Dame, Notre Dame, IN Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (8) Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556. (9) Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (10) Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. (11) Central Research Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730 Beijing, China. (12) Ministry of Education Key Laboratory of Bioinformatics, School of Life Sciences and Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, 100084 Beijing, China. (13) Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556; xlu@nd.edu. Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202.
