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• W4308397175 abstract "<h3>Background</h3> Diacylglycerol kinases (DGK) convert diacylglycerol (DAG) into phosphatidic acid which limits DAG-induced propagation of T cell activation.¹ T cells predominantly express DGK alpha and DGK zeta isoforms (DGKalpha/zeta),² and deletion of either enhances T cell activation and function.^3,4 DGKalpha/zeta are overexpressed in tumor infiltrating T cells and may limit the anti-tumor activity of these cells.⁵ Thus, inhibition of DGKalpha/zeta is a potential therapeutic avenue to enhance T cell anti-tumor responses. We demonstrate that inhibition of DGKalpha/zeta with novel dual DGKalpha/zeta inhibitors (DGKi) enhances anti-tumor T cell activity. <h3>Methods</h3> The role of DGKalpha/zeta in T cell activation was studied using wildtype and CRISPR-knockout T cells. <i>In vitro</i> studies assessing the effect of DGKi were conducted using various mouse and human T cell functional assays. T cell exhaustion studies were performed in T cells from lymphocytic choriomeningitis virus (LCMV) clone 13-infected mice.<i> In vivo</i> activity of DGKi was assessed by measuring T cell activation in OT-I mice challenged with OVA-peptides. Efficacy studies and memory rechallenge experiments were performed in the MC38 syngeneic tumor model. <h3>Results</h3> CRISPR knockout studies characterizing the role of DGKalpha/zeta on T cells demonstrated that both isoforms regulate T cell activation and function. DGKi enhanced IFN gamma production by human melanoma-specific T cells stimulated with the weak affinity MART1 antigen. Similarly, treatment of mouse OT-I cells with DGKi enhanced responses to low-affinity OVA-peptides and OT-I-mediated cytotoxicity of MC38-OVA tumor cells. Treatment of exhausted CD8 T cells with DGKi reverted exhaustion caused by chronic LCMV infection, and enhanced T cell function with PDL1 blockade. DGKi rescued cytokine release from T cells suppressed by adenosine, TGF beta or PGE₂ treatment. Oral administration of DGKi resulted in dose-dependent increase in T cell activation in mice. Furthermore, DGKi in combination with anti-PD-1 therapy was efficacious in the MC38 model with complete tumor regressions in treated animals. These mice eradicated tumors upon rechallenge with MC38 cells two months later, demonstrating durable anti-tumor memory responses. <h3>Conclusions</h3> We demonstrate that DGKalpha/zeta negatively regulates T cell activity. Dual DGKalpha/zeta inhibition restores T cell responses to weak tumor antigens, overcomes cell exhaustion, and enhances CD8 T cell cytotoxic activity. <i>In vivo</i> efficacy data demonstrates that DGKi in combination with anti-PD-1 antibody therapy promotes robust anti-tumor responses and generates durable T cell memory. These data support dual DGKalpha/zeta inhibition in combination with anti-PD-1 antibodies as a therapeutic approach for cancer treatment. <h3>References</h3> Mérida I, Avila-Flores A, Merino E. Diacylglycerol kinases: at the hub of cell signalling. <i>Biochem J</i>. 2008; <b>409</b>(1):1–18. Krishna S, Zhong X. Role of diacylglycerol kinases in T cell development and function. <i>Crit Rev Immunol</i>. 2013; <b>33</b>(2):97–118. Guo R, Wan C-K, Carpenter JH, <i>et al</i>. Synergistic control of T cell development and tumor suppression by diacylglycerol kinase alpha and zeta. <i>Proc Natl Acad Sci U S A</i>. 2008; <b>105</b>(33):11909–14. Riese MJ, Grewal J, Das J, <i>et al</i>. Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses. <i>J Biol Chem</i>. 2011; <b>286</b>(7):5254–65. Prinz PU, Mendler AN, Masouris I, <i>et al</i>. High DGK-α and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8+ T cells that is reversible by pharmacologic intervention. <i>J Immunol</i>. 2012; <b>188</b>(12):5990–6000. <h3>Ethics Approval</h3> All animal studies were approved and conducted in accordance with the Explora IACUC Program of Veterinary Care." @default.
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• W4308397175 date "2022-11-01" @default.
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• W4308397175 title "855 Diacylglycerol kinase alpha and zeta dual inhibitors enhance T cell responses and promote robust and durable anti-tumor T cell immunity" @default.
• W4308397175 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0855" @default.
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