Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8⁺ T cell stemness and antitumor immunity
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 pr...
Saved in:
| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 11; pp. 6047 - 6055 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
17.03.2020
|
| Subjects | |
| Online Access | Get full text |
Cover
Loading…
| 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. |
|---|---|
| AbstractList | 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. 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 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 T SCM 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. 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. 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 ) 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 and While deletion of 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 T 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. Current approaches for producing T cells for adoptive immunotherapy for cancer rely on interleukin (IL)-2–based strategies that generate large numbers of tumor-reactive T cells but also drive the cells toward terminal differentiation and exhaustion, thereby diminishing their effectiveness. By characterizing the metabolic effects of IL-2 versus IL-21, a closely related cytokine that expands cells but lacks the detrimental effects of IL-2, we identified a pivotal role of lactate dehydrogenase (LDH) in regulating CD8 + T cell effector differentiation. Remarkably, LDH inhibition combined with IL-21 enhanced the formation of T memory stem cells and mitochondrial fitness while suppressing programs of exhaustion and senescence and markedly enhancing antitumor responses. These findings have potential therapeutic implications. 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 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 T SCM 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. |
| Author | Fioravanti, Jessica Leonard, Warren J. Rabinowitz, Joshua D. Lin, Jian-Xin Ebina-Shibuya, Risa Neckers, Leonard M. Veenbergen, Sharon Gromer, Daniel Bleck, Christopher Oh, Jangsuk Hermans, Dalton Gattinoni, Luca Christensen, Stephen Nguyen, Rosa Gautam, Sanjivan García-Cañaveras, Juan C. Mitra, Suman Li, Peng Spolski, Rosanne Du, Ning |
| Author_xml | – sequence: 1 givenname: Dalton surname: Hermans fullname: Hermans, Dalton – sequence: 2 givenname: Sanjivan surname: Gautam fullname: Gautam, Sanjivan – sequence: 3 givenname: Juan C. surname: García-Cañaveras fullname: García-Cañaveras, Juan C. – sequence: 4 givenname: Daniel surname: Gromer fullname: Gromer, Daniel – sequence: 5 givenname: Suman surname: Mitra fullname: Mitra, Suman – sequence: 6 givenname: Rosanne surname: Spolski fullname: Spolski, Rosanne – sequence: 7 givenname: Peng surname: Li fullname: Li, Peng – sequence: 8 givenname: Stephen surname: Christensen fullname: Christensen, Stephen – sequence: 9 givenname: Rosa surname: Nguyen fullname: Nguyen, Rosa – sequence: 10 givenname: Jian-Xin surname: Lin fullname: Lin, Jian-Xin – sequence: 11 givenname: Jangsuk surname: Oh fullname: Oh, Jangsuk – sequence: 12 givenname: Ning surname: Du fullname: Du, Ning – sequence: 13 givenname: Sharon surname: Veenbergen fullname: Veenbergen, Sharon – sequence: 14 givenname: Jessica surname: Fioravanti fullname: Fioravanti, Jessica – sequence: 15 givenname: Risa surname: Ebina-Shibuya fullname: Ebina-Shibuya, Risa – sequence: 16 givenname: Christopher surname: Bleck fullname: Bleck, Christopher – sequence: 17 givenname: Leonard M. surname: Neckers fullname: Neckers, Leonard M. – sequence: 18 givenname: Joshua D. surname: Rabinowitz fullname: Rabinowitz, Joshua D. – sequence: 19 givenname: Luca surname: Gattinoni fullname: Gattinoni, Luca – sequence: 20 givenname: Warren J. surname: Leonard fullname: Leonard, Warren J. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32123114$$D View this record in MEDLINE/PubMed |
| BookMark | eNpdkc2OEzEQhC20iM0GzpxAlrhwmd1u2-MZX5BQ-FspEpflbHlmnMRRxg62BxRuvBaPw5PgKEv4ObT60F-VulRX5MIHbwl5inCN0PCbvTfpGhUDgRyxeUBmCAorKRRckBkAa6pWMHFJrlLaAoCqW3hELjlDVngxI2Fp-myypYPdHIYY1rY4Wur8xnUuu-BpOngb1-6bTfSryxt6u6wY0hzoPoYxFOXiTfvz-w96R3u729GU7ehtStT4oUx2eRpDpG4cJ-_y4TF5uDK7ZJ_c7zn59O7t3eJDtfz4_nbxeln1QvBcIbbYt3UNwFcApu9BCNmZplNWDbIHWde2U0OLtWpNg3LFVo0VUsLAOEch-Zy8Ovnup260Q299jman99GNJh50ME7_e_Fuo9fhi26gFSixGLy8N4jh82RT1qNLx4TG2zAlzXgDQtVQ84K--A_dhin6Eu9IKQmclxxzcnOi-hhSinZ1fgZBH8vUxzL1nzKL4vnfGc787_YK8OwEbFMO8XxnUjHFpeK_AA1Dp6g |
| CitedBy_id | crossref_primary_10_1002_ctm2_1614 crossref_primary_10_1146_annurev_immunol_110519_071134 crossref_primary_10_1016_j_intimp_2023_110622 crossref_primary_10_1111_imcb_12551 crossref_primary_10_3389_fimmu_2021_745109 crossref_primary_10_1038_s41573_021_00339_6 crossref_primary_10_3389_fimmu_2023_1137037 crossref_primary_10_3390_cancers13133230 crossref_primary_10_1007_s00262_021_02881_z crossref_primary_10_1186_s12943_023_01844_5 crossref_primary_10_3389_fimmu_2023_1267816 crossref_primary_10_3390_antib10020017 crossref_primary_10_1016_j_ccell_2023_04_001 crossref_primary_10_1016_j_cytogfr_2022_11_001 crossref_primary_10_3389_fimmu_2023_1063454 crossref_primary_10_1016_j_ejca_2022_11_032 crossref_primary_10_3389_fonc_2023_1253783 crossref_primary_10_1101_cshperspect_a041530 crossref_primary_10_1016_j_ejca_2022_08_034 crossref_primary_10_1186_s12967_020_02672_7 crossref_primary_10_3390_ijms242417422 crossref_primary_10_1016_j_cmet_2023_06_003 crossref_primary_10_1002_JLB_5MR0321_145R crossref_primary_10_1038_s42003_023_04747_9 crossref_primary_10_1016_j_trecan_2024_03_010 crossref_primary_10_1073_pnas_2319254121 crossref_primary_10_1016_j_canlet_2022_215978 crossref_primary_10_1016_j_biopha_2024_116782 crossref_primary_10_1016_j_biopha_2022_114164 crossref_primary_10_1186_s13045_021_01179_y crossref_primary_10_1590_1414_431x2022e12320 crossref_primary_10_3390_cancers14010183 crossref_primary_10_1016_j_ymthe_2021_08_003 crossref_primary_10_1038_s41388_022_02312_y crossref_primary_10_1097_CM9_0000000000002989 crossref_primary_10_1016_j_canlet_2023_216396 crossref_primary_10_3389_fimmu_2023_1264882 crossref_primary_10_1016_j_bbcan_2024_189084 crossref_primary_10_1007_s12094_024_03569_3 crossref_primary_10_3389_fimmu_2022_1016646 crossref_primary_10_3389_fmed_2021_778500 crossref_primary_10_3390_cells11193103 crossref_primary_10_3389_fonc_2021_667715 crossref_primary_10_1186_s12943_021_01464_x crossref_primary_10_1084_jem_20220686 crossref_primary_10_20517_cdr_2023_60 crossref_primary_10_1007_s13402_022_00667_8 crossref_primary_10_1016_j_lfs_2021_120057 crossref_primary_10_1016_j_canlet_2020_12_021 crossref_primary_10_3390_ijms23115970 crossref_primary_10_3389_fimmu_2023_1121565 crossref_primary_10_3390_cancers15153898 crossref_primary_10_3389_fonc_2021_813897 crossref_primary_10_1038_s41590_023_01536_8 crossref_primary_10_3389_fcell_2022_1013885 crossref_primary_10_1038_s41423_021_00833_2 crossref_primary_10_1038_s41577_021_00537_8 crossref_primary_10_3389_fimmu_2022_900826 crossref_primary_10_1016_j_banm_2021_01_018 crossref_primary_10_3389_fimmu_2021_653605 crossref_primary_10_1186_s13148_020_00971_w crossref_primary_10_1002_1878_0261_13691 crossref_primary_10_3389_fonc_2021_723888 crossref_primary_10_1016_j_celrep_2021_109210 crossref_primary_10_1007_s00251_021_01248_z crossref_primary_10_1016_j_clim_2022_109078 crossref_primary_10_1158_2326_6066_CIR_20_0791 crossref_primary_10_4049_jimmunol_2000459 crossref_primary_10_1038_s41419_023_06142_y crossref_primary_10_1007_s10753_022_01680_7 crossref_primary_10_1021_acs_jmedchem_0c00916 crossref_primary_10_1016_j_ejphar_2023_175991 crossref_primary_10_1111_imr_13356 crossref_primary_10_1016_j_semcancer_2022_12_001 crossref_primary_10_1186_s13046_022_02439_6 crossref_primary_10_3390_cancers13061229 crossref_primary_10_1126_science_ade3697 crossref_primary_10_1016_j_jbc_2023_105488 crossref_primary_10_1084_jem_20221839 crossref_primary_10_1038_s41563_024_01825_z crossref_primary_10_3390_cells10092334 crossref_primary_10_1111_imm_13575 crossref_primary_10_3389_fonc_2023_1175532 crossref_primary_10_1016_j_cmet_2022_07_012 crossref_primary_10_1016_j_molmed_2024_03_008 crossref_primary_10_1136_jitc_2021_002591 crossref_primary_10_1155_2022_4930932 crossref_primary_10_1016_j_bbrc_2022_03_113 crossref_primary_10_1016_j_fsi_2022_04_041 crossref_primary_10_1158_2326_6066_CIR_20_0561 crossref_primary_10_1186_s12964_023_01354_3 crossref_primary_10_1016_j_copbio_2020_10_011 crossref_primary_10_1016_j_jdermsci_2021_07_007 crossref_primary_10_1016_j_ejphar_2022_175482 crossref_primary_10_1016_j_medj_2024_03_001 crossref_primary_10_1515_biol_2022_0636 crossref_primary_10_1038_s41419_022_04632_z crossref_primary_10_4049_jimmunol_2300339 crossref_primary_10_1097_CJI_0000000000000402 crossref_primary_10_1038_s42255_020_0216_7 crossref_primary_10_3389_fimmu_2023_1104771 crossref_primary_10_1038_s41586_021_03861_0 crossref_primary_10_1155_2022_9086540 crossref_primary_10_1016_j_semcancer_2022_09_001 crossref_primary_10_1016_j_bcp_2022_115197 crossref_primary_10_3390_cancers13050941 crossref_primary_10_1038_s41423_024_01148_8 crossref_primary_10_3389_fonc_2022_1036477 crossref_primary_10_1126_sciimmunol_adi8217 crossref_primary_10_1039_D0MD00221F crossref_primary_10_1038_s41573_023_00746_x crossref_primary_10_3390_jcm10143058 crossref_primary_10_1136_jitc_2020_002155 crossref_primary_10_3389_fonc_2023_1235711 crossref_primary_10_1016_j_cellimm_2024_104816 crossref_primary_10_1016_j_ecoenv_2024_116500 crossref_primary_10_1136_jitc_2020_002157 crossref_primary_10_3390_antib10030025 crossref_primary_10_1097_CCO_0000000000000877 crossref_primary_10_1097_MOH_0000000000000615 crossref_primary_10_1016_j_biopha_2023_114824 crossref_primary_10_1111_jcmm_15780 crossref_primary_10_3389_fimmu_2021_691134 crossref_primary_10_1002_hep_32348 crossref_primary_10_3892_ol_2024_14244 crossref_primary_10_1038_s41577_021_00539_6 crossref_primary_10_1016_j_cellimm_2021_104314 |
| Cites_doi | 10.1016/j.immuni.2013.01.004 10.18632/oncotarget.24442 10.1038/nri2922 10.1038/nrd4296 10.1038/s41586-018-0597-x 10.1038/nm.4241 10.1038/s41467-017-01477-5 10.1073/pnas.1301138111 10.1182/blood-2006-10-054973 10.1073/pnas.1620498114 10.1084/jem.20151159 10.1182/blood-2009-09-241398 10.1016/j.immuni.2019.03.028 10.12688/f1000research.12202.1 10.1021/acs.jmedchem.7b00941 10.1016/j.celrep.2015.12.095 10.1126/science.aaf6284 10.1038/nature12297 10.1182/blood-2007-09-113050 10.1172/jci.insight.124405 10.1186/gb-2009-10-3-r25 10.1084/jem.20112607 10.1038/s41586-019-1311-3 10.1093/bioinformatics/btp616 10.1093/nar/gkv468 10.1089/ars.2017.7014 10.15252/embj.201488349 10.1101/cshperspect.a028449 10.1016/j.cell.2017.12.025 10.1016/j.immuni.2009.08.005 10.1111/j.1600-065X.2012.01155.x 10.1038/s41467-018-06841-7 10.1016/j.cell.2014.07.048 10.1021/acs.analchem.7b00396 10.1038/nri.2016.70 10.1158/0008-5472.CAN-19-0217 10.1016/j.immuni.2011.12.007 10.1016/j.immuni.2014.06.005 10.1172/JCI69589 10.1038/s41590-018-0311-z 10.1038/ni.3682 10.1016/j.cell.2016.05.035 10.1038/nature20165 10.1038/s41586-019-1678-1 10.1038/nm.1982 10.1182/blood-2015-11-683847 |
| ContentType | Journal Article |
| Copyright | Copyright National Academy of Sciences Mar 17, 2020 2020 |
| Copyright_xml | – notice: Copyright National Academy of Sciences Mar 17, 2020 – notice: 2020 |
| DBID | NPM AAYXX CITATION 7QG 7QL 7QP 7QR 7SN 7SS 7T5 7TK 7TM 7TO 7U9 8FD C1K FR3 H94 M7N P64 RC3 7X8 5PM |
| DOI | 10.1073/pnas.1920413117 |
| DatabaseName | PubMed CrossRef Animal Behavior Abstracts Bacteriology Abstracts (Microbiology B) Calcium & Calcified Tissue Abstracts Chemoreception Abstracts Ecology Abstracts Entomology Abstracts (Full archive) Immunology Abstracts Neurosciences Abstracts Nucleic Acids Abstracts Oncogenes and Growth Factors Abstracts Virology and AIDS Abstracts Technology Research Database Environmental Sciences and Pollution Management Engineering Research Database AIDS and Cancer Research Abstracts Algology Mycology and Protozoology Abstracts (Microbiology C) Biotechnology and BioEngineering Abstracts Genetics Abstracts MEDLINE - Academic PubMed Central (Full Participant titles) |
| DatabaseTitle | PubMed CrossRef Virology and AIDS Abstracts Oncogenes and Growth Factors Abstracts Technology Research Database Nucleic Acids Abstracts Ecology Abstracts Neurosciences Abstracts Biotechnology and BioEngineering Abstracts Environmental Sciences and Pollution Management Entomology Abstracts Genetics Abstracts Animal Behavior Abstracts Bacteriology Abstracts (Microbiology B) Algology Mycology and Protozoology Abstracts (Microbiology C) AIDS and Cancer Research Abstracts Chemoreception Abstracts Immunology Abstracts Engineering Research Database Calcium & Calcified Tissue Abstracts MEDLINE - Academic |
| DatabaseTitleList | CrossRef Virology and AIDS Abstracts PubMed |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Sciences (General) |
| EISSN | 1091-6490 |
| EndPage | 6055 |
| ExternalDocumentID | 10_1073_pnas_1920413117 32123114 26929369 |
| Genre | Journal Article |
| GroupedDBID | --- -DZ -~X .55 0R~ 123 29P 2AX 2FS 2WC 4.4 53G 5RE 5VS 85S AACGO AAFWJ AANCE ABBHK ABOCM ABPLY ABPPZ ABTLG ABXSQ ABZEH ACGOD ACIWK ACNCT ACPRK ADACV AENEX AEUPB AEXZC AFFNX AFOSN AFRAH ALMA_UNASSIGNED_HOLDINGS AQVQM BKOMP CS3 D0L DCCCD DIK DOOOF DU5 E3Z EBS F5P FRP GX1 H13 HH5 HYE IPSME JAAYA JBMMH JENOY JHFFW JKQEH JLS JLXEF JPM JSG JST KQ8 L7B LU7 N9A N~3 O9- OK1 PNE PQQKQ R.V RHF RHI RNA RNS RPM RXW SA0 SJN TAE TN5 UKR VQA W8F WH7 WOQ WOW X7M XSW Y6R YBH YKV YSK ZCA ~02 ~KM NPM AAYXX CITATION 7QG 7QL 7QP 7QR 7SN 7SS 7T5 7TK 7TM 7TO 7U9 8FD C1K FR3 H94 M7N P64 RC3 7X8 5PM |
| ID | FETCH-LOGICAL-c443t-1181c855003f00acc0446ba7b9e9d6c0655eb9d81598a716f2f7e4660d2331463 |
| IEDL.DBID | RPM |
| ISSN | 0027-8424 |
| IngestDate | Tue Sep 17 21:25:57 EDT 2024 Fri Aug 16 21:54:04 EDT 2024 Thu Oct 10 22:17:13 EDT 2024 Fri Dec 06 02:30:21 EST 2024 Sat Sep 28 08:28:57 EDT 2024 Tue Dec 10 23:45:03 EST 2024 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 11 |
| Keywords | LDH IL-2 immunometabolism IL-21 adoptive immunotherapy |
| Language | English |
| License | Published under the PNAS license. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c443t-1181c855003f00acc0446ba7b9e9d6c0655eb9d81598a716f2f7e4660d2331463 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewers: M.A.C., City of Hope National Medical Center; and T.F., University of Pittsburgh. 2Present address: Unidad de Biomarcadores y Medicina de Precisión, Unidad Analítica, Instituto de Investigación Sanitaria Fundación Hospital La Fe, 46026 Valencia, Spain. 3D.G. and S.M. contributed equally to this work. Contributed by Warren J. Leonard, January 16, 2020 (sent for review December 9, 2019; reviewed by Michael A. Caligiuri and Toren Finkel) 6Present address: Department of Inflammation and Immunology, Pfizer, Cambridge, MA 02139. 1D.H. and S.G. contributed equally to this work. Author contributions: D.H., S.G., J.C.G.-C., D.G., S.M., R.S., P.L., R.N., J.-X.L., S.V., J.F., L.M.N., J.D.R., L.G., and W.J.L. designed research; D.H., S.G., J.C.G.-C., D.G., S.M., R.S., P.L., R.N., J.-X.L., J.O., N.D., S.V., J.F., R.E.-S., and C.B. performed research; L.M.N. contributed new reagents/analytic tools; D.H., S.G., J.C.G.-C., D.G., S.M., R.S., P.L., S.C., R.N., J.-X.L., S.V., J.F., C.B., J.D.R., L.G., and W.J.L. analyzed data; and D.H., S.G., J.C.G.-C., D.G., R.S., P.L., J.-X.L., C.B., L.M.N., J.D.R., L.G., and W.J.L. wrote the paper. 4Present address: Department of Medicine, Massachusetts General Hospital, Boston, MA 02114. 5Present address: University of Lille, UMR-S-1172-JPARc-Center de Researche Jean-Pierre Aubert Neuroscience et Cancer, F-59000 Lille, France. 7Present address: Laboratory of Pediatric Gastroenterology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands. |
| ORCID | 0000-0002-5740-7448 0000-0001-7112-1537 0000-0003-1029-3444 0000-0001-9639-7249 |
| OpenAccessLink | https://www.pnas.org/content/pnas/117/11/6047.full.pdf |
| PMID | 32123114 |
| PQID | 2379603300 |
| PQPubID | 42026 |
| PageCount | 9 |
| ParticipantIDs | pubmedcentral_primary_oai_pubmedcentral_nih_gov_7084161 proquest_miscellaneous_2370495053 proquest_journals_2379603300 crossref_primary_10_1073_pnas_1920413117 pubmed_primary_32123114 jstor_primary_26929369 |
| PublicationCentury | 2000 |
| PublicationDate | 2020-03-17 |
| PublicationDateYYYYMMDD | 2020-03-17 |
| PublicationDate_xml | – month: 03 year: 2020 text: 2020-03-17 day: 17 |
| PublicationDecade | 2020 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States – name: Washington |
| PublicationTitle | Proceedings of the National Academy of Sciences - PNAS |
| PublicationTitleAlternate | Proc Natl Acad Sci U S A |
| PublicationYear | 2020 |
| Publisher | National Academy of Sciences |
| Publisher_xml | – sequence: 0 name: National Academy of Sciences – name: National Academy of Sciences |
| References | Zhang L. (e_1_3_4_22_2) 2016; 14 Buck M. D. (e_1_3_4_5_2) 2015; 212 Song M. (e_1_3_4_33_2) 2018; 562 Zeng R. (e_1_3_4_14_2) 2007; 109 Leonard W. J. (e_1_3_4_10_2) 2019; 50 Liu Y. (e_1_3_4_34_2) 2018; 9 Mathis D. (e_1_3_4_1_2) 2011; 11 Bailis W. (e_1_3_4_40_2) 2019; 571 Tran E. (e_1_3_4_7_2) 2017; 18 Loschinski R. (e_1_3_4_23_2) 2018; 9 Patten D. A. (e_1_3_4_24_2) 2014; 33 Langmead B. (e_1_3_4_44_2) 2009; 10 Spolski R. (e_1_3_4_12_2) 2014; 13 Liao W. (e_1_3_4_15_2) 2014; 111 Robinson M. D. (e_1_3_4_45_2) 2010; 26 van der Windt G. J. (e_1_3_4_19_2) 2012; 36 Gautam S. (e_1_3_4_29_2) 2019; 20 Finlay D. K. (e_1_3_4_18_2) 2012; 209 Lu W. (e_1_3_4_41_2) 2018; 28 Welsh R. M. (e_1_3_4_32_2) 2009; 31 Wang R. (e_1_3_4_6_2) 2012; 249 Spolski R. (e_1_3_4_11_2) 2017; 6 Sabatino M. (e_1_3_4_38_2) 2016; 128 Buck M. D. (e_1_3_4_21_2) 2016; 166 Gattinoni L. (e_1_3_4_30_2) 2009; 15 Sukumar M. (e_1_3_4_36_2) 2013; 123 Mognol G. P. (e_1_3_4_31_2) 2017; 114 Wang Y. H. (e_1_3_4_46_2) 2014; 158 O’Sullivan D. (e_1_3_4_20_2) 2014; 41 Lin J. X. (e_1_3_4_43_2) 2017; 8 Zhang D. (e_1_3_4_35_2) 2019; 574 Hanada K. I. (e_1_3_4_28_2) 2019; 4 Lin J. X. (e_1_3_4_9_2) 2018; 10 Gattinoni L. (e_1_3_4_39_2) 2017; 23 O’Neill L. A. (e_1_3_4_2_2) 2016; 16 Kim J. (e_1_3_4_4_2) 2018; 2018 Hinrichs C. S. (e_1_3_4_8_2) 2008; 111 Markley J. C. (e_1_3_4_16_2) 2010; 115 Peng M. (e_1_3_4_37_2) 2016; 354 Yeung C. (e_1_3_4_26_2) 2019; 79 Tyrakis P. A. (e_1_3_4_27_2) 2016; 540 Su X. (e_1_3_4_42_2) 2017; 89 Lee Y. S. (e_1_3_4_3_2) 2018; 172 Metsalu T. (e_1_3_4_47_2) 2015; 43 Rai G. (e_1_3_4_25_2) 2017; 60 Liao W. (e_1_3_4_13_2) 2013; 38 Zeng H. (e_1_3_4_17_2) 2013; 499 |
| References_xml | – volume: 38 start-page: 13 year: 2013 ident: e_1_3_4_13_2 article-title: Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy publication-title: Immunity doi: 10.1016/j.immuni.2013.01.004 contributor: fullname: Liao W. – volume: 9 start-page: 13125 year: 2018 ident: e_1_3_4_23_2 article-title: IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner publication-title: Oncotarget doi: 10.18632/oncotarget.24442 contributor: fullname: Loschinski R. – volume: 11 start-page: 81 year: 2011 ident: e_1_3_4_1_2 article-title: Immunometabolism: An emerging frontier publication-title: Nat. Rev. Immunol. doi: 10.1038/nri2922 contributor: fullname: Mathis D. – volume: 13 start-page: 379 year: 2014 ident: e_1_3_4_12_2 article-title: Interleukin-21: A double-edged sword with therapeutic potential publication-title: Nat. Rev. Drug Discov. doi: 10.1038/nrd4296 contributor: fullname: Spolski R. – volume: 562 start-page: 423 year: 2018 ident: e_1_3_4_33_2 article-title: IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity publication-title: Nature doi: 10.1038/s41586-018-0597-x contributor: fullname: Song M. – volume: 23 start-page: 18 year: 2017 ident: e_1_3_4_39_2 article-title: T memory stem cells in health and disease publication-title: Nat. Med. doi: 10.1038/nm.4241 contributor: fullname: Gattinoni L. – volume: 8 start-page: 1320 year: 2017 ident: e_1_3_4_43_2 article-title: Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells publication-title: Nat. Commun. doi: 10.1038/s41467-017-01477-5 contributor: fullname: Lin J. X. – volume: 111 start-page: 3508 year: 2014 ident: e_1_3_4_15_2 article-title: Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression publication-title: Proc. Natl. Acad. Sci. U.S.A. doi: 10.1073/pnas.1301138111 contributor: fullname: Liao W. – volume: 109 start-page: 4135 year: 2007 ident: e_1_3_4_14_2 article-title: The molecular basis of IL-21–mediated proliferation publication-title: Blood doi: 10.1182/blood-2006-10-054973 contributor: fullname: Zeng R. – volume: 114 start-page: E2776 year: 2017 ident: e_1_3_4_31_2 article-title: Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells publication-title: Proc. Natl. Acad. Sci. U.S.A. doi: 10.1073/pnas.1620498114 contributor: fullname: Mognol G. P. – volume: 212 start-page: 1345 year: 2015 ident: e_1_3_4_5_2 article-title: T cell metabolism drives immunity publication-title: J. Exp. Med. doi: 10.1084/jem.20151159 contributor: fullname: Buck M. D. – volume: 115 start-page: 3508 year: 2010 ident: e_1_3_4_16_2 article-title: IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice publication-title: Blood doi: 10.1182/blood-2009-09-241398 contributor: fullname: Markley J. C. – volume: 50 start-page: 832 year: 2019 ident: e_1_3_4_10_2 article-title: The γc family of cytokines: Basic biology to therapeutic ramifications publication-title: Immunity doi: 10.1016/j.immuni.2019.03.028 contributor: fullname: Leonard W. J. – volume: 6 start-page: 1872 year: 2017 ident: e_1_3_4_11_2 article-title: The γ c family of cytokines: Fine-tuning signals from IL-2 and IL-21 in the regulation of the immune response publication-title: F1000 Res. doi: 10.12688/f1000research.12202.1 contributor: fullname: Spolski R. – volume: 60 start-page: 9184 year: 2017 ident: e_1_3_4_25_2 article-title: Discovery and optimization of potent, cell-active pyrazole-based inhibitors of lactate dehydrogenase (LDH) publication-title: J. Med. Chem. doi: 10.1021/acs.jmedchem.7b00941 contributor: fullname: Rai G. – volume: 14 start-page: 1206 year: 2016 ident: e_1_3_4_22_2 article-title: Mammalian target of rapamycin complex 2 controls CD8 T cell memory differentiation in a Foxo1-dependent manner publication-title: Cell Rep. doi: 10.1016/j.celrep.2015.12.095 contributor: fullname: Zhang L. – volume: 354 start-page: 481 year: 2016 ident: e_1_3_4_37_2 article-title: Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism publication-title: Science doi: 10.1126/science.aaf6284 contributor: fullname: Peng M. – volume: 499 start-page: 485 year: 2013 ident: e_1_3_4_17_2 article-title: mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function publication-title: Nature doi: 10.1038/nature12297 contributor: fullname: Zeng H. – volume: 111 start-page: 5326 year: 2008 ident: e_1_3_4_8_2 article-title: IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy publication-title: Blood doi: 10.1182/blood-2007-09-113050 contributor: fullname: Hinrichs C. S. – volume: 4 start-page: 124405 year: 2019 ident: e_1_3_4_28_2 article-title: An effective mouse model for adoptive cancer immunotherapy targeting neoantigens publication-title: JCI Insight doi: 10.1172/jci.insight.124405 contributor: fullname: Hanada K. I. – volume: 10 start-page: R25 year: 2009 ident: e_1_3_4_44_2 article-title: Ultrafast and memory-efficient alignment of short DNA sequences to the human genome publication-title: Genome Biol. doi: 10.1186/gb-2009-10-3-r25 contributor: fullname: Langmead B. – volume: 209 start-page: 2441 year: 2012 ident: e_1_3_4_18_2 article-title: PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells publication-title: J. Exp. Med. doi: 10.1084/jem.20112607 contributor: fullname: Finlay D. K. – volume: 571 start-page: 403 year: 2019 ident: e_1_3_4_40_2 article-title: Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function publication-title: Nature doi: 10.1038/s41586-019-1311-3 contributor: fullname: Bailis W. – volume: 26 start-page: 139 year: 2010 ident: e_1_3_4_45_2 article-title: edgeR: A Bioconductor package for differential expression analysis of digital gene expression data publication-title: Bioinformatics doi: 10.1093/bioinformatics/btp616 contributor: fullname: Robinson M. D. – volume: 43 start-page: W566-70 year: 2015 ident: e_1_3_4_47_2 article-title: ClustVis: A web tool for visualizing clustering of multivariate data using principal component analysis and heatmap publication-title: Nucleic Acids Res. doi: 10.1093/nar/gkv468 contributor: fullname: Metsalu T. – volume: 28 start-page: 167 year: 2018 ident: e_1_3_4_41_2 article-title: Extraction and quantitation of nicotinamide adenine dinucleotide redox cofactors publication-title: Antioxid. Redox Signal. doi: 10.1089/ars.2017.7014 contributor: fullname: Lu W. – volume: 33 start-page: 2676 year: 2014 ident: e_1_3_4_24_2 article-title: OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand publication-title: EMBO J. doi: 10.15252/embj.201488349 contributor: fullname: Patten D. A. – volume: 10 start-page: a028449 year: 2018 ident: e_1_3_4_9_2 article-title: The common cytokine receptor γ chain family of cytokines publication-title: Cold Spring Harb. Perspect. Biol. doi: 10.1101/cshperspect.a028449 contributor: fullname: Lin J. X. – volume: 172 start-page: 22 year: 2018 ident: e_1_3_4_3_2 article-title: An integrated view of immunometabolism publication-title: Cell doi: 10.1016/j.cell.2017.12.025 contributor: fullname: Lee Y. S. – volume: 31 start-page: 178 year: 2009 ident: e_1_3_4_32_2 article-title: Blimp hovers over T cell immunity publication-title: Immunity doi: 10.1016/j.immuni.2009.08.005 contributor: fullname: Welsh R. M. – volume: 249 start-page: 14 year: 2012 ident: e_1_3_4_6_2 article-title: Metabolic reprogramming and metabolic dependency in T cells publication-title: Immunol. Rev. doi: 10.1111/j.1600-065X.2012.01155.x contributor: fullname: Wang R. – volume: 9 start-page: 4429 year: 2018 ident: e_1_3_4_34_2 article-title: Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth publication-title: Nat. Commun. doi: 10.1038/s41467-018-06841-7 contributor: fullname: Liu Y. – volume: 158 start-page: 1309 year: 2014 ident: e_1_3_4_46_2 article-title: Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis publication-title: Cell doi: 10.1016/j.cell.2014.07.048 contributor: fullname: Wang Y. H. – volume: 89 start-page: 5940 year: 2017 ident: e_1_3_4_42_2 article-title: Metabolite spectral accuracy on orbitraps publication-title: Anal. Chem. doi: 10.1021/acs.analchem.7b00396 contributor: fullname: Su X. – volume: 16 start-page: 553 year: 2016 ident: e_1_3_4_2_2 article-title: A guide to immunometabolism for immunologists publication-title: Nat. Rev. Immunol. doi: 10.1038/nri.2016.70 contributor: fullname: O’Neill L. A. – volume: 79 start-page: 5060 year: 2019 ident: e_1_3_4_26_2 article-title: Targeting glycolysis through inhibition of lactate dehydrogenase impairs tumor growth in preclinical models of Ewing sarcoma publication-title: Cancer Res. doi: 10.1158/0008-5472.CAN-19-0217 contributor: fullname: Yeung C. – volume: 36 start-page: 68 year: 2012 ident: e_1_3_4_19_2 article-title: Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development publication-title: Immunity doi: 10.1016/j.immuni.2011.12.007 contributor: fullname: van der Windt G. J. – volume: 41 start-page: 75 year: 2014 ident: e_1_3_4_20_2 article-title: Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development publication-title: Immunity doi: 10.1016/j.immuni.2014.06.005 contributor: fullname: O’Sullivan D. – volume: 123 start-page: 4479 year: 2013 ident: e_1_3_4_36_2 article-title: Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function publication-title: J. Clin. Invest. doi: 10.1172/JCI69589 contributor: fullname: Sukumar M. – volume: 20 start-page: 337 year: 2019 ident: e_1_3_4_29_2 article-title: The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity publication-title: Nat. Immunol. doi: 10.1038/s41590-018-0311-z contributor: fullname: Gautam S. – volume: 2018 start-page: 8605471 year: 2018 ident: e_1_3_4_4_2 article-title: Regulation of immune cell functions by metabolic reprogramming publication-title: J. Immunol. Res. contributor: fullname: Kim J. – volume: 18 start-page: 255 year: 2017 ident: e_1_3_4_7_2 article-title: “Final common pathway” of human cancer immunotherapy: Targeting random somatic mutations publication-title: Nat. Immunol. doi: 10.1038/ni.3682 contributor: fullname: Tran E. – volume: 166 start-page: 63 year: 2016 ident: e_1_3_4_21_2 article-title: Mitochondrial dynamics controls T cell fate through metabolic programming publication-title: Cell doi: 10.1016/j.cell.2016.05.035 contributor: fullname: Buck M. D. – volume: 540 start-page: 236 year: 2016 ident: e_1_3_4_27_2 article-title: S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate publication-title: Nature doi: 10.1038/nature20165 contributor: fullname: Tyrakis P. A. – volume: 574 start-page: 575 year: 2019 ident: e_1_3_4_35_2 article-title: Metabolic regulation of gene expression by histone lactylation publication-title: Nature doi: 10.1038/s41586-019-1678-1 contributor: fullname: Zhang D. – volume: 15 start-page: 808 year: 2009 ident: e_1_3_4_30_2 article-title: Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells publication-title: Nat. Med. doi: 10.1038/nm.1982 contributor: fullname: Gattinoni L. – volume: 128 start-page: 519 year: 2016 ident: e_1_3_4_38_2 article-title: Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies publication-title: Blood doi: 10.1182/blood-2015-11-683847 contributor: fullname: Sabatino M. |
| SSID | ssj0009580 |
| Score | 2.6772993 |
| Snippet | Interleukin (IL)-2 and IL-21 dichotomously shape CD8⁺ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective... Interleukin (IL)-2 and IL-21 dichotomously shape CD8 T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective... Interleukin (IL)-2 and IL-21 dichotomously shape CD8 + T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective... Interleukin (IL)-2 and IL-21 dichotomously shape CD8+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective... Current approaches for producing T cells for adoptive immunotherapy for cancer rely on interleukin (IL)-2–based strategies that generate large numbers of... |
| SourceID | pubmedcentral proquest crossref pubmed jstor |
| SourceType | Open Access Repository Aggregation Database Index Database Publisher |
| StartPage | 6047 |
| SubjectTerms | Adoptive transfer Anticancer properties Antitumor activity Biological Sciences CD8 antigen Cell differentiation Clonal deletion Cytokines Dehydrogenase Dehydrogenases Differentiation (biology) Effector cells Exhaustion Gene expression Glycolysis Immunity Immunological memory Immunotherapy Inhibition Interleukin 2 Interleukin 21 L-Lactate dehydrogenase Lactate dehydrogenase Lactic acid Lymphocytes Lymphocytes T Memory cells Metabolism Nuclear receptors Oxidative phosphorylation PD-1 protein Phosphorylation Pyruvic acid Receptors Stem cells Tricarboxylic acid cycle Tumors |
| Title | Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8⁺ T cell stemness and antitumor immunity |
| URI | https://www.jstor.org/stable/26929369 https://www.ncbi.nlm.nih.gov/pubmed/32123114 https://www.proquest.com/docview/2379603300 https://search.proquest.com/docview/2370495053 https://pubmed.ncbi.nlm.nih.gov/PMC7084161 |
| Volume | 117 |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1Nb9QwEB21PXFBFCgE2spIHIpQdh3biZMjWqgKahGHVuotchxHG4lNVrvpYfn1nXE-YBEnDpEixYmSzNjzxn7zDPAerUpZgw6zSolQmdiGRYxn3OhMWC9BR7XDN9-Tqzv17T6-P4B4rIXxpH1b1LPm52rW1EvPrVyv7Hzkic1_3Cw0p8WyaH4Ihxh-xxR9UtpN-7oTgcOvEmrU89Fyvm7MdoaQhisSmaH99ySN3FGk9qJST0z8F-T8mzn5Ryi6fAZPBwzJPvXvegwHrnkOx0Mv3bKLQUr6wwtYXRtLaJKVbrkrNy16C0YtVjfLuvBcLbbdUfFf_QvvoylZ9vU6FBHrWrb2PD3HFp_Tj-yW0QQ_I9FnGhqZaUo8iGWwajes9jUm3e4l3F1-uV1chcMGC6FVSnYhFZ1aUjTjsuLcWEuru4XRReayMrGITmJXZGWKkCc1mFhVotJOJQkvhZQ4xMoTOGraxr0G_AxujHbYziECo3pZm5Q2iaoqpW1JkwAuxh-cr3sdjdyvf2uZk1ny32YJ4MQbYGonEsRwMskCOB0tkg89bZsLqTEJk5LzAN5Nl7GP0H8xjWsffBtMhBDryQBe9QacHj56QAB6z7RTA9Lf3r-Cbul1uAc3fPPfd76FJ4LSd6IH6lM46jYP7gwxTlecU4SJz71nPwKrNvng |
| link.rule.ids | 230,314,727,780,784,885,27924,27925,53791,53793 |
| linkProvider | National Library of Medicine |
| linkToHtml | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3Pb9MwFLbGOMAFMWAQGGAkDkMorWM7dnJEhamDduLQSbtFjuOokWhStd2h--v3nvMDijhxiBQpdpT4Pdvfs7_3mZCPYFWMGnSYlpKH0sQ2zGO4Y0an3HoJOswdnl-p6bX8fhPfHJG4z4XxpH2bV6P612pUV0vPrVyv7LjniY1_ziea4WZZNH5AHsZCp1EfpA9au0mbecJhAJZc9oo-WozXtdmOANQwiTIzeAKfwLE7iuTBvNRSE_8FOv_mTv4xGV08JU86FEm_tF97Qo5c_YycdP10S887MelPz8lqZiziSVq45b7YNOAvMG_Rql5WuWdr0e0e0_-qO6iHi7L0chbyiO4auvZMPUcnX5PPdEFxiZ-i7DMOjtTUBVzIM1g1G1r5LJPd_gW5vvi2mEzD7oiF0EopdiGmnVrUNGOiZMxYi_u7udF56tJCWcAnscvTIgHQkxgIrUpeaieVYgUXAgZZcUqO66Z2rwj8BjNGOyjnAINhxqxVhVVRWSZ4MKkKyHnfwNm6VdLI_A64FhmaJfttloCcegMM5bgCFCdUGpCz3iJZ19e2GQcXUEwIxgLyYXgMvQTbxdSuufVlIBQCtCcC8rI14PDy3gMCog9MOxRABe7DJ-CYXom7c8TX_13zPXk0Xcxn2ezy6scb8phjMI9kQX1GjnebW_cWEM8uf-f9-x4TovxP |
| linkToPdf | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1Nb9QwELWgSIgLokAhUMBIHIpQNo6d2MkRbVm1sK16aKXeIsdxtJHYJNpND8uvZ8b5oIs4cYgUKXaUeMb2G_vNMyGfwKoYNSg_LSPuRzo2fh7DHdMq5cZJ0GHu8MWlPLuJvt_Gt_eO-nKkfZNXs_rnelZXK8etbNcmGHliwdXFXDHcLAuDtiiDh-RRLMDJxkB90ttN-uwTDoNwxKNR1UeJoK31dgbAhkUoNYOn8Akcv8Mw2pubenriv4Dn3_zJexPS4hl5OiBJ-rX_4kPywNbPyeHQV7f0ZBCU_vyCrJfaIKakhV3tik0DPgNzF63qVZU7xhbd7jAFsPoF9XBhlp4vfR7SrqGtY-tZOj9NvtBrisv8FKWfcYCkui7gQq7ButnQymWadLuX5Gbx7Xp-5g_HLPgmikTnY-qpQV0zJkrGtDG4x5trlac2LaQBjBLbPC0SAD6JhvCq5KWykZSs4ELAQCuOyEHd1PY1gd9gWisL5SzgMMyaNbIwMizLBA8nlR45GRs4a3s1jcztgiuRoVmyP2bxyJEzwFSOS0ByQqYeOR4tkg39bZtxcAHJhGDMIx-nx9BTsF10bZs7VwbCIUB8wiOvegNOLx89wCNqz7RTAVTh3n8CzunUuAdnfPPfNT-Qx1eni2x5fvnjLXnCMZ5HvqA6Jgfd5s6-A9DT5e-de_8Gv2v9Yg |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Lactate+dehydrogenase+inhibition+synergizes+with+IL-21+to+promote+CD8%E2%81%BA+T+cell+stemness+and+antitumor+immunity&rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences+-+PNAS&rft.au=Hermans%2C+Dalton&rft.au=Gautam%2C+Sanjivan&rft.au=Garc%C3%ADa-Ca%C3%B1averas%2C+Juan+C.&rft.au=Gromer%2C+Daniel&rft.date=2020-03-17&rft.pub=National+Academy+of+Sciences&rft.issn=0027-8424&rft.eissn=1091-6490&rft.volume=117&rft.issue=11&rft.spage=6047&rft.epage=6055&rft_id=info:doi/10.1073%2Fpnas.1920413117&rft.externalDocID=26929369 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0027-8424&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0027-8424&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0027-8424&client=summon |