01
Deblina Raychaudhuri, et al.
Nat Immunol. 2024.
Activation and functional differentiation of CD8+ T cells are implicated in metabolic pathways leading to lactate production. Lactation is a histone post-translational modification derived from lactic acid. In their study, the activation of human and mouse CD8+ T cells, especially H3K18la and H3K9la, resulted in increased histone lactation, especially H3K18la and H3K9la, either by anti-CD3 plus anti-CD28 stimulation or antigen-specific stimulation. The production of lactate during T cell activation is associated with the enrichment of these lactoacylation markers. In the OT-I model, higher levels of H3K18la and H3K9la are observed in IFNγ+CD8+ T cells within the lymph nodes drained by MB49-ova tumors compared to control MB49 tumors. In GvHD mice, the abundance of activated GZMB+ and TBET+ CD8+ T cells in the liver is increased, while H3K18la and H3K9la levels are increased. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analyses showed that H3K18la and H3K9la acted as transcription promoters in CD8+ T cells. They found that H3K18la tagged genes critical for T cell activation, such as Stat1, Cd28, Icos, Pdcd1, and Pfkfb2, while H3K9la was rich in genes such as Ifng and genes associated with naïve and memory T cells, including Tcf7, Ccr7, and Batf3. Different regions, including promoter and enhancer regions, are tagged by these emulsylation markers, which show different RNApol II occupancy patterns compared to other hPTMs, suggesting a synergistic role in driving gene transcription. H3K9la is enriched in both the initial and activated states, with different gene associations. In naïve CD8+ T cells, H3K18la is associated with genes encoding molecules involved in T cell quiescence, whereas in activated CD8+ T cells, H3K18na is rich in genes encoding effector molecules. Memory CD8+ T cells show an enrichment of the H3K9la peak in memory T cell genes. In contrast, depleted CD8+ T cells depleted the H3K18la and H3K9la markers. H3K9la is associated with mitochondrial metabolism-related genes in naïve cells and memory cells, while H3K18la is associated with glycolytic enzyme-encoding genes in activated cells. These lactation markers play an important role in regulating mitochondrial dynamics and energy metabolism in different T cell states. They also found that endogenous lactate production is essential for histone lactation. Exogenous lactate has different effects on T cell subsets. In activated CD8+ T cells with intracellular lactate of high glycolytic origin, exogenous lactate does not affect histone lactation, but in naïve and memory subsets with hypoglycolysis, exogenous lactate affects histone lactation. By targeting metabolic and epigenetic pathways to regulate H3K18la and H3K9la levels, the authors modulate CD8+ T cell effector function and anti-tumor immunity. LDHA inhibition reduces H3K18la levels, depleting them from activation-related gene promoters, and reduces the production of cytotoxic effector molecules and T cell-mediated cytotoxicity. In contrast, inhibition of histone deacetylase (HDAC1–HDAC3) increases H3K18la and H3K9la, enhancing effector gene expression and cytotoxicity. In vivo treatment of MB49 tumor-bearing mice with the HDAC inhibitor MS275 results in an increase in intratumoral GZMB+ effector CD8+ T cells with increased levels of H3K18la and H3K9la in tumor-derived and TDLN-derived CD8+ T cells. Overall, this study highlights the importance of histone lactation in CD8+ T cells.
DOI: 10.1038/s41590-024-01985-9.
02
Xueliang Wang, et al.
Nature. 2024.
Immune checkpoint blockade (ICB) therapy has emerged as one of the most promising strategies for cancer treatment. However, more than 85% of colorectal cancer patients are microsatellite stable (MSS), and the vast majority of microsatellite stable colorectal cancer patients are not sensitive to anti-PD-1 therapy and are not suitable for ICB therapy. Several studies have shown that gut microbiota significantly influences host responsiveness to ICB therapy. Therefore, they hypothesized that Fusobacterium nucleatum Fn may affect CD8+ T cell function through its metabolites, thereby regulating the sensitivity of MSS CRC to ICB therapy. To test this hypothesis, they; Using the results of a clinical trial of 25 patients with microsatellite stable colorectal cancer, it was shown that a high abundance of nucleatium nucleatium in tumors predicted a favorable response to anti-PD-1 therapy. Fecal microbial transplantation (FMT) experiments showed that compared with mice transplanted with feces with low abundance of patients with RCD, feces with high abundance of RCC patients significantly enhanced the sensitivity of colorectal cancer mice to anti-PD-1 treatment. In addition, Fusobacterium nucleatum and its metabolites, especially butyric acid, enhanced the efficacy of anti-PD-1 in a variety of tumor models (germ-free mice, SPF mice, and immunized humanized mice). Co-culture of T cells from the same colorectal cancer patient and colorectal cancer organoids has demonstrated that Fusobacterium nucleatum can promote anti-PD-1 efficacy through its metabolites, especially butyric acid, providing strong evidence for preclinical studies. Mechanistically, this study demonstrated that Fusobacterium nucleatum produced abundant butyric acid, inhibited HDAC3/8 activity in CD8+ T cells, and then enhanced the acetylation of H3K27 at the TBX21 promoter and promoted the expression of TBX21. The high level of TBX21 inhibits the high expression of PD-1 in tumor-infiltrating CD8+ T cells, alleviates the depletion of CD8+ T cells, enhances its sensitivity to anti-PD-1 treatment, secretes a large number of GZMB, TNFα and IFN-γ, and exerts a tumor-killing effect. Tissue microarray combined with fluorescence in situ hybridization (FISH) technology further confirmed that the abundance of Fusobacterium nucleatum was negatively correlated with the PD-1 expression level in patients with microsatellite stable colorectal cancer. In order to verify the key role of butyric acid in the promotion of anti-PD-1 by Fusobacterium nuclari, the research team knocked out the key gene for butyric acid production in Fusobacterium nuclarium, and confirmed that the knockout of this gene would eliminate its anti-PD-1 enhancement effect.
DOI: 10.1016/j.ccell.2024.08.019.
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