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Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]

ABSTRACT: The differentiation into effector and memory CD8+ T cell subsets was recently associated with specific metabolic pathways to sustain their diverse bioenergetics needs. Clonally expanding T cells rely strongly on glucose and glutamine utilization to maintain high cell proliferation and effector functions. We found that proliferating effector CD8+ T cells, in addition to oxidizing, also reductively carboxylate glutamine, to maintain rapid lipid synthesis for cell proliferation. Interfering with reductive carboxylation by genetic deletion of isocitrate dehydrogenase 2 (IDH2), the enzyme mediating this reaction in the mitochondria, surprisingly did not impair proliferation and effector function upon infection, but skewed the CD8+ T cell response towards enhanced memory differentiation. Pharmacological IDH2 inhibition during in vitro CAR T cell manufacturing also induced memory features and thus strongly enhanced their antitumor activity and persistence upon adoptive cell transfer into murine melanoma tumour models. Mechanistically, IDH2 inhibition caused a disequilibrium in metabolites regulating histone-modifying enzymes, which altered the epigenetic landscape, increasing chromatin accessibility at genes required for memory differentiation. Restoring this metabolite balance or preventing the epigenetic modifications abrogated the enhanced CD8+ T cell memory differentiation and anti-tumour activity induced by IDH2 inhibition. These findings suggest that reductive carboxylation of glutamine in activated CD8+ T cells is dispensable for their effector function, but instead primarily instructs a metabolite composition that epigenetically locks them in a terminal effector differentiation program. Blocking this metabolic route allows for increased memory formation, which can be exploited to optimize CAR T cell production for adoptive cell transfer immunotherapy against cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE192394 | GEO | 2023/07/17

REPOSITORIES: GEO

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Project description:The optimal T cell attributes for the adoptive immunotherapy of cancer and viral diseases are currently unclear. Recent adoptive transfer clinical trials using ex vivo expanded tumor infiltrating lymphocytes has provided evidence that differentiated effector T cells can mediate durable responses in selected cancer patients. The capacity of these transferred cells to persist in the host was found to strongly correlate with their clinical activity. Thus, there is significant interest in identifying intrinsic markers that define antigen specific effector T cells that can develop into long-lived memory cells rather than undergoing apoptosis after infusion in humans. We recently reported the long term persistence of ex vivo expanded tumor specific CD8+ T effector clones in refractory metastatic melanoma patients after adoptive T cell transfer. By utilizing these highly homogeneous clone populations, we sought to define the pre-infusion cellular and molecular attributes associated with their effector to memory transition. Comparative transcriptional profiling found the pre-infusion clone mRNA expression levels of the IL-7 receptor (IL-7Ra) and the proto-oncogene, c-myc, directly correlated with the level of clonal persistence after adoptive transfer in humans. The predictive value of these markers was further established by utilizing IL-7R protein, induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor specific effector clones that could engraft after controlled adoptive transfer into highly immunodeficient mice. These findings support that IL-7R and c-myc expression are valuable cell intrinsic markers that can predict the fate of effector CD8+ T cells after adoptive transfer. We used microarrays to compare the pre-infusion gene expression profile of melanoma-specific CD8+ T cell clones that would eventually either persist or not after adoptive transfer in humans. We derived ten melanoma-specific CD8+ T cell clones and determined their degree of persistence after adoptive therapy into patients. We performed microarray on the pre-infusion samples of six persisting and four non-persisting clones to obtain a comparative gene signature profile.

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Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]

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