Dataset Information

Vaccine adjuvant-elicited CD8⁺ T cell immunity is co-dependent on T-bet and FOXO1.

ABSTRACT: T-bet and FOXO1 are transcription factors canonically associated with effector and memory T cell fates, respectively. During an infectious response, these factors direct the development of CD8⁺ T cell fates, where T-bet deficiency leads to ablation of only short-lived effector cells, while FOXO1 deficiency results in selective loss of memory. In contrast, following adjuvanted subunit vaccination in mice, both effector- and memory-fated T cells are compromised in the absence of either T-bet or FOXO1. Thus, unlike responses to challenge with Listeria monocytogenes, productive CD8⁺ T cell responses to adjuvanted vaccination require coordinated regulation of FOXO1 and T-bet transcriptional programs. Single-cell RNA sequencing analysis confirms simultaneous T-bet, FOXO1, and TCF1 transcriptional activity in vaccine-elicited, but not infection-elicited, T cells undergoing clonal expansion. Collectively, our data show that subunit vaccine adjuvants elicit T cell responses dependent on transcription factors associated with effector and memory cell fates.

SUBMITTER: Ivanova DL

PROVIDER: S-EPMC10577800 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Vaccine adjuvant-elicited CD8<sup>+</sup> T cell immunity is co-dependent on T-bet and FOXO1.

Ivanova Daria L DL Thompson Scott B SB Klarquist Jared J Harbell Michael G MG Kilgore Augustus M AM Lasda Erika L EL Hesselberth Jay R JR Hunter Christopher A CA Kedl Ross M RM

Cell reports 20230729 8

T-bet and FOXO1 are transcription factors canonically associated with effector and memory T cell fates, respectively. During an infectious response, these factors direct the development of CD8<sup>+</sup> T cell fates, where T-bet deficiency leads to ablation of only short-lived effector cells, while FOXO1 deficiency results in selective loss of memory. In contrast, following adjuvanted subunit vaccination in mice, both effector- and memory-fated T cells are compromised in the absence of either ...[more]

PMID: 37516968

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Project description:Background: Immune checkpoint blockers (ICBs) are revolutionized therapeutic strategies for cancer, but most patients with solid neoplasms remain resistant to ICBs, partly because of the difficulty in reversing the highly immunosuppressive tumor microenvironment (TME). Exploring the strategies for tumor immunotherapy is highly dependent on the discovery of molecular mechanisms of tumor immune escape and potential therapeutic target. Krüppel-like Factor 5 (KLF5) is a cell-intrinsic oncogene to promote tumorigenesis. However, the cell-extrinsic effects of KLF5 on suppressing the immune response to cancer remain unclear. Methods: We analyzed the immunosuppressive role of KLF5 in mice models transplanted with KLF5-deleted/overexpressing tumor cells. We performed RNA sequencing, immunohistochemistry, western blotting, real time-PCR, ELISA, luciferase assay, chromatin immunoprecipitation (ChIP), and flow cytometry to demonstrate the effects of KLF5 on CD8+ T cell infiltration and related molecular mechanism. Single-cell RNA sequencing and spatial transcriptomics analysis were applied to further decipher the association between KLF5 expression and infiltrating immune cells. The efficacy of KLF5/COX2 inhibitors combined with anti-programmed cell death protein 1 (anti-PD1) therapy were explored in pre-clinical models. Finally, a gene-expression signature depending on KLF5/COX2 axis and associated immune markers was created to predict patient survival. Results: KLF5 inactivation decelerated basal-like breast tumor growth in a CD8+ T-cell-dependent manner. Transcriptomic profiling revealed that KLF5 loss in tumors increases the number and activated function of T lymphocytes. Mechanistically, KLF5 binds to the promoter of the COX2 gene and promotes COX2 transcription; subsequently, KLF5 deficiency decreases prostaglandin E2 (PGE2) release from tumor cells by reducing COX2 expression. Inhibition of the KLF5/COX2 axis increases the number and functionality of intratumoral antitumor T cells to synergize the antitumorigenic effects of anti-PD1 therapy. Analysis of patient datasets at single-cell and spatial resolution shows that low expression of KLF5 is associated with an immune-supportive TME. Finally, we generate a KLF5/COX2-associated immune score (KC-IS) to predict patient survival. Conclusions: Our results identified a novel mechanism responsible for KLF5-mediated immunosuppression in TME, and targeting the KLF5/COX2/PGE2 axis is a critical immunotherapy sensitizer.

Dataset Information

Vaccine adjuvant-elicited CD8⁺ T cell immunity is co-dependent on T-bet and FOXO1.

Publications

Vaccine adjuvant-elicited CD8<sup>+</sup> T cell immunity is co-dependent on T-bet and FOXO1.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Vaccine adjuvant-elicited CD8+ T cell immunity is co-dependent on T-bet and FOXO1.

Publications

Vaccine adjuvant-elicited CD8<sup>+</sup> T cell immunity is co-dependent on T-bet and FOXO1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Vaccine adjuvant-elicited CD8⁺ T cell immunity is co-dependent on T-bet and FOXO1.