01
The authors found that P4HA1 is strongly induced upon activation and depletion of CD8 + T cells. Upregulation was confirmed by RNA sequencing analysis and flow cytometry using CART cells as a model. P4HA1 expression was correlated with CD8 + T cell depletion and cancer progression in both mouse models and human samples. In tumor-draining lymph nodes and tumors, P4HA1+T cells increased while TCF 1 + cells were decreased. In patient-derived xenograft tumors, higher levels of P4HA1 + CD8 + T cells were found in metastatic tumors.Knockdown or chemical inhibition of P4HA1 enhanced CD8 + T cell progenitor cell expansion and improved terminal depletion. P4HA1 knockdown in CART cells leads in increased expansion and increased stem-like central and central memory populations. The chemical inhibitor DPCA has a similar effect, increasing progenitor and memory cells while reducing effector cells. CAR-T cells treated with DPCA exhibited resistance to depletion and enhanced cytotoxicity. P4HA1 accumulates in the mitochondria upon activation of CD8 + T cells, disrupting mitochondrial fitness. The authors found that it was enriched in mitochondria and inhibition of P4HA1 improved mitochondrial respiration and morphology. P4HA1-mediatedαKG-succinate metabolism dysregulates the tricarboxylic acid (TCA) cycle, and DPCA treatment decreases succinate and increasesαKG levels. In vitro depletion or chemical inhibition of P4HA1 enhanced the in vivo efficacy and persistence of CART cells. In the CART model, P4HA1 inhibition leads in complete and persistent tumor clearance and increased blood persistence. In vivo treatment with P4HA1 inhibitors activated endogenous T cell immunity and reduced tumor recurrence and metastasis in a syngeneic mouse model. The P4HA1 inhibitors produce a systemic immune response through the expansion of CD8 + T progenitor cells in the TDLN and peripheral blood. P4HA1 is associated with anti-PD-1 resistance and has higher expression in non-responsive tumors. Circulating P4HA1 + CD8 + T cells may serve as a biomarker for cancer progression and immune checkpoint blockade (ICB) resistance.
Together, studies highlight the importance of P4HA1 in CD8 + T cell biology and its potential as a target for improving cancer immunotherapy. Understanding the role of P4HA1 in T cell depletion and mitochondrial metabolism provides new insights into the development of more effective immunotherapeutic strategies. The results suggest that targeting P4HA1 can enhance adoptive and endogenous T cell responses to enhance antitumor immunity, which may provide better therapeutic effects in cancer patients.
DOI: 10.1016/j.ccell.2024.12.001
02
The authors found that deamidated IRF3 was unable to bind homologous response elements within the promoter of inflammatory genes. The use of deamidated IRF3-N85D and anti-deamidated IRF3-N85A mutants suggests that deamidation inhibits IRF3-mediated IFN and ISG expression. IRF3-N85D was unable to induce antiviral gene expression, while IRF3-N85A was more strongly activated its expression. Deamidation does not affect phosphorylation, dimerization, or nuclear translocation of IRF3 but weakens its ability to bind DNA, as shown in chromatin immunoprecipitation and gel migration assays. Then, deamidation inhibited the IRF 3-mediated antiviral response in vivo. Construction of the IRF 3-N85D andIRF 3-N85A knock-in mice revealed that deamidation inhibited the IRF3-mediated antiviral response in vivo. IFN induction was reduced in Irf3N85D / N85D mouse-derived bone marrow-derived macrophages (BMDM) upon viral infection as compared with wild-type and Irf3N85A / N85A mice. In vivo, Irf3N85D / N85D mice showedincreased viral replication and decreased survival upon VSV and HSV-1 infection, whereas IRF3-N85A / N85A mice exhibited an enhanced antiviral response. Finally, the authors suppressed CTPS 1during innate immune activation to promote IFN induction. Infection inhibition of CTPS 1 activity in IRF 3 deamidation and CTP synthesiscorrelated with the altered IR charge status of IRF 3, reduced interaction between IRF 3 and CTPS 1, and decreased CTP synthesis activity. During immune activation, GSK3β phosphorylates CTPS 1 at serine 575, and inhibition of GSK3β abolished this phosphorylation and affects IRF3 deamidation. CTPS 1-S575A (an anti-phosphosomemutant) inhibited IFN induction more strongly than wild-type CTPS 1, highlighting the role of CTPS 1 phosphorylation in regulating IFN induction. Overall, the studies revealed a novel role for CTPS1 in inhibiting antiviral interferon induction by deaminating IRF3. The CTPS 1 activity is regulated during immune activation, and its inhibition promotes IFN induction and hostimmune defense.
These findings expand our understanding of the interplay between cellular metabolism and innate immune responses, and provide potential therapeutic strategies for antiviral therapy. However, further studies are still needed to determine the relevance of these findings in humans and non-human primates, and to explore the tissue-specific functions of CTPS 1.
DOI: 10.1016/j.immuni.2024.11.020
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