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Whether metabolic pathways regulate\n                      <jats:italic>Gzmb<\/jats:italic>\n                      expression in CTLs is incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A tumor-specific CTL and tumor coculture model and a tumor-bearing mouse model were used to determine the role of glucose-6-phosphate dehydrogenase (G6PD) in CTL function and tumor immune evasion. A link between granzyme B expression and patient survival was analyzed in human patients with epithelioid mesothelioma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mesothelioma cells alone are sufficient to activate tumor-specific CTLs and to enhance aerobic glycolysis to induce a PD-1\n                      <jats:sup>hi<\/jats:sup>\n                      Gzmb\n                      <jats:sup>lo<\/jats:sup>\n                      CTL phenotype. However, inhibition of lactate dehydrogenase A, the key enzyme of the aerobic glycolysis pathway, has no significant effect on tumor-induced CTL activation. Tumor cells induce H3K9me3 deposition at the promoter of\n                      <jats:italic>G6pd<\/jats:italic>\n                      , the gene that encodes the rate-limiting enzyme G6PD in the pentose phosphate pathway, to downregulate\n                      <jats:italic>G6pd<\/jats:italic>\n                      expression in tumor-specific CTLs. G6PD activation increases acetyl-coenzyme A (CoA) production to increase H3K9ac deposition at the\n                      <jats:italic>Gzmb<\/jats:italic>\n                      promoter and to increase\n                      <jats:italic>Gzmb<\/jats:italic>\n                      expression in tumor-specific CTLs converting them from a Gzmb\n                      <jats:sup>lo<\/jats:sup>\n                      to a Gzmb\n                      <jats:sup>hi<\/jats:sup>\n                      phenotype, thus increasing CTL tumor lytic activity. Activation of G6PD increases Gzmb\n                      <jats:sup>+<\/jats:sup>\n                      tumor-specific CTLs and suppresses tumor growth in tumor-bearing mice. Consistent with these findings,\n                      <jats:italic>GZMB<\/jats:italic>\n                      expression level was found to correlate with increased survival in patients with epithelioid mesothelioma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>G6PD is a metabolic checkpoint in tumor-activated CTLs. The H3K9me3\/G6PD\/acetyl-CoA\/H3K9ac\/Gzmb pathway is particularly important in CTL activation and immune evasion in epithelioid mesothelioma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2021-003543","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T11:35:56Z","timestamp":1641900956000},"page":"e003543","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["G6PD functions as a metabolic checkpoint to regulate granzyme B expression in tumor-specific cytotoxic T lymphocytes"],"prefix":"10.1136","volume":"10","author":[{"given":"Chunwan","family":"Lu","sequence":"first","affiliation":[{"name":"School of Life Sciences, Tianjin University, Tianjin, China"},{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, 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