Browsing by Author "Chaudhary, Seema"

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    Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers
    (National Academy of Sciences, 2018-10-02) 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; Pathology and Laboratory Medicine, School of Medicine
    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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    Opposing roles of TGFβ and BMP signaling in prostate cancer development
    (Cold Spring Harbor Laboratory Press, 2017-12-01) Lu, Xin; Jin, Eun-Jung; Cheng, Xi; Feng, Shan; Shang, Xiaoying; Deng, Pingna; Jiang, Shan; Chang, Qing; Rahmy, Sharif; Chaudhary, Seema; Lu, Xuemin; Zhao, Ren; Wang, Y. Alan; DePinho, Ronald A.; Medicine, School of Medicine
    SMAD4 constrains progression of Pten-null prostate cancer and serves as a common downstream node of transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways. Here, we dissected the roles of TGFβ receptor II (TGFBR2) and BMP receptor II (BMPR2) using a Pten-null prostate cancer model. These studies demonstrated that the molecular actions of TGFBR2 result in both SMAD4-dependent constraint of proliferation and SMAD4-independent activation of apoptosis. In contrast, BMPR2 deletion extended survival relative to Pten deletion alone, establishing its promoting role in BMP6-driven prostate cancer progression. These analyses reveal the complexity of TGFβ-BMP signaling and illuminate potential therapeutic targets for prostate cancer.