In addition to canonical activation and cytokine signaling, immune cell phenotype and function are exquisitely tuned to nutrient and metabolic conditions. In this regard, our previous work revealed that glutamine antagonism could markedly condition the differentiation of effector CD8 T cells, enhancing long-lived, memory-like phenotypes and improving intra-tumoral survival and proliferative capacity in mouse tumor models (Leone, et al., Science, 2019). Building on these observations, our lab is interested in elucidating specific molecular mechanisms of adaptive immune response to metabolic perturbations. Of particular interest are metabolically dependent mechanisms of T cell differentiation. Our approach includes assessment of transcription factor modulation, metabolic enzyme moonlighting, metabolically responsive enzymatic processes resulting in altered posttranslational modifications (e.g., methylation, acetylation), spliceosomal modulation, cellular stress response, as well as bioactive lipid signaling, and cancer/immune cell co-metabolism. This work requires integration of a broad range of techniques including high-dimensional flow cytometry, mass spectrometry (e.g., metabolomics, stable isotope tracing, multiple reaction monitoring), metabolic flux analyses, advanced proteomics, single-cell transcriptomics and epigenomics, CRISPR/Cas9 gene editing, microscopy, and metabolic imaging agents. We employ an extensive range of immunologic models in mice, in vitro studies, as well as patient samples. Our goal is to elucidate fundamental cellular processes activated in response to metabolic events that have broad implications for development of immune-based therapeutics.
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Leone RD, Powell JD.Metabolism of immune cells in cancer. Nat Rev Cancer. 2020 Sep;20(9):516-531
Leone RD, Zhao L, Englert JM, Sun IM, Oh MH, Sun IH, Arwood ML, Bettencourt IA, Patel CH, Wen J, Tam A, Blosser RL, Prchalova E, Alt J, Rais R, Slusher BS, Powell JD.Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019 Nov 22;366(6468):1013-1021
Leone RD, Sun IM, Oh MH, Sun IH, Wen J, Englert J, Powell JD. Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models. Cancer Immunol Immunother. August 2018;67:1271-84
Leone RD, Horton MR, Powell JD. Something in the air: hyperoxic conditioning of the tumor microenvironment for enhanced immunotherapy. Cancer Cell. 2015 Apr 13;27(4):435-6
Leone RD, Powell JD. Metabolism of Tumor Immunity. In Cancer Immunotherapy Principles and Practice, 2nd Edition. L. H. Butterfield, H. L. Kaufman, F. M. Marincola, P. A. Ascierto, & R. K. Puri (Eds.), (pp. 410-420). New York: Springer Publishing Company
Methods for cancer and immunotherapy using prodrugs of glutamine analogs.
Patent # 10,842,763 |
Slusher B, Powell J, Tenora L, Majer P, Jancarik A, Leone RD, Englert J, inventors. The Johns Hopkins University, assignee. Methods for cancer and immunotherapy using prodrugs of glutamine analogs. United States 10,842,763. 2020 November.
Metal Organothiol Particles
Patent # 6,369,206 |
Leone RD, Hainfeld JF. US Patent 6,369,206, Metal Organothiol Particles. April 9, 2002.
Small Organometallic Probes.
Patent # 5,521,289 |
Hainfeld JF, Leone RD, Furuya FR, Powell RD. US Patent 5,521,289. Small Organometallic Probes. May 28, 1996.