5 results on '"Neckers, Leonard M."'
Search Results
2. Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity.
- Author
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Hermans, Dalton, Gautam, Sanjivan, García-Cañaveras, Juan C., Gromer, Daniel, Mitra, Suman, Spolski, Rosanne, Peng Li, Christensen, Stephen, Nguyen, Rosa, Jian-Xin Lin, Jangsuk Oh, Ning Du, Veenbergen, Sharon, Fioravanti, Jessica, Ebina-Shibuya, Risa, Bleck, Christopher, Neckers, Leonard M., Rabinowitz, Joshua D., Gattinoni, Luca, and Leonard, Warren J.
- Subjects
LACTATE dehydrogenase ,T cells ,T cell differentiation ,KREBS cycle ,AEROBIC metabolism - Abstract
Interleukin (IL)-2 and IL-21 dichotomously shape CD8+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (T
SCM ) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effectorlike metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1. While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21- induced metabolism but caused major transcriptomic changes, including the suppression of IL-21-induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokinemediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cellbased immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
3. Charged linker sequence modulates eukaryotic heat shock protein 90 (Hsp90) chaperone activity.
- Author
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Tsutsumi, Shinji, Mollapour, Mehdi, Prodromou, Chrisostomos, Chung-Tien Lee, Panaretou, Barry, Yoshida, Soichiro, Mayer, Matthias P., and Neckers, Leonard M.
- Subjects
HEAT shock proteins ,EUKARYOTIC cells ,MOLECULAR chaperones ,PLASMODIUM ,BIOLOGICAL divergence ,EUKARYOTES - Abstract
Hsp90 is an essential and highly conserved modular molecular chaperone whose N and middle domains are separated by a disordered region termed the charged linker. Although its importance has been previously disregarded, because a minimal linker length is sufficient for Hsp90 activity, the evolutionary persistence of extensive charged linkers of divergent sequence in Hsp90 proteins of most eukaryotes remains unexplained. To examine this question further, we introduced human and plasmodium native and length-matched artificial linkers into yeast Hsp90. After evaluating ATPase activity and biophysical characteristics in vitro, and chaperone function in vivo, we conclude that linker sequence affects Hsp90 function, cochaperone interaction, and conformation. We propose that the charged linker, in addition to providing the flexibility necessary for Hsp90 domain rearrangements-likely its original purpose-has evolved in eukaryotes to serve as a rheostat for the Hsp90 chaperone machine. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
4. Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells.
- Author
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De Leon, Johanny Tonos, Iwai, Aki, Feau, Clementine, Garcia, Yenni, Balsiger, Heather A., Storer, Cheryl L., Suro, Raquel M., Garza, Kristine M., Sunmin Lee, Yeong Sang Kim, Yu Chen, Yang-Min Ning, Riggs, Daniel L., Fletterick, Robert J., Guy, R. Kiplin, Trepel, Jane B., Neckers, Leonard M., and Cox, Marc B.
- Subjects
HEAT shock proteins ,PROSTATE cancer ,CANCER cells ,PROTEIN binding ,STEROID hormones ,GENE expression ,CELL proliferation - Abstract
Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
5. Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8 + T cell stemness and antitumor immunity.
- Author
-
Hermans D, Gautam S, García-Cañaveras JC, Gromer D, Mitra S, Spolski R, Li P, Christensen S, Nguyen R, Lin JX, Oh J, Du N, Veenbergen S, Fioravanti J, Ebina-Shibuya R, Bleck C, Neckers LM, Rabinowitz JD, Gattinoni L, and Leonard WJ
- Subjects
- Animals, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes transplantation, Cell Differentiation drug effects, Cell Differentiation immunology, Cell Line, Tumor transplantation, Humans, Immunologic Memory, Immunotherapy, Adoptive methods, Interleukin-2 immunology, Interleukin-2 metabolism, Interleukins immunology, L-Lactate Dehydrogenase metabolism, Melanoma, Experimental immunology, Mice, Primary Cell Culture, Stem Cells drug effects, Stem Cells metabolism, CD8-Positive T-Lymphocytes immunology, Enzyme Inhibitors pharmacology, Interleukins metabolism, L-Lactate Dehydrogenase antagonists & inhibitors, Melanoma, Experimental therapy, Stem Cells immunology
- Abstract
Interleukin (IL)-2 and IL-21 dichotomously shape CD8
+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM ) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1 While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21-induced metabolism but caused major transcriptomic changes, including the suppression of IL-21-induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21., Competing Interests: Competing interest statement: W.J.L. is an inventor on patents or patent applications related to IL-2 and IL-21. D.H., S.G., L.M.N., L.G., and W.J.L. are inventors on patent application(s) related to the LDH inhibitor described herein. L.G. is an inventor on a patent related to methods for generating TSCM cells.- Published
- 2020
- Full Text
- View/download PDF
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