Shuh Narumiya

Pancreatic cancers, whose incidence increases with age, are often refractory to treatment. Here, we identified a core mechanism shared by physiological homeostasis, senescent cell accumulation during aging, and pancreatic cancers. Pancreatic acinar cells, when stressed, secrete CXCL13, which protects stressed cells while transiently activating paracrine Hippo/YAP signaling to induce proliferation and PD-L1–mediated immune protection to maintain organ homeostasis. In the aged pancreas, CXCL13/YAP/PD-L1 signaling permits senescent cells to survive, driving feedforward chronic inflammation and steatosis. Because of prolonged CXCL13/YAP/PD-L1 activation in pancreatic cancers, neighboring noncancerous cells, activated for proliferation and immune-protected, eventually transform and accelerate tumor progression. CXCL13 blockade removed senescent cells and ameliorated steatosis in the aged pancreas while suppressing tumor growth in pancreatic cancer models, highlighting the CXCL13/YAP/PD-L1 axis as a potential therapeutic target. Together, our findings demonstrate the stress-induced CXCL13/YAP/PD-L1 axis as a central regulator of cell-state transitions in the pancreas, providing a unifying principle by which organ homeostasis, aging, and tumorigenesis are governed.

Foxp3 ⁺ regulatory T cells (Tregs) heavily infiltrate malignant tumors and restrict antitumor immunity. These tumor-infiltrating Tregs (TI-Tregs) adopt a distinct phenotype by expressing a unique set of genes. This TI-Treg gene expression signature is conserved in TI-Tregs across species and tumor types and stages, suggesting the presence of a common inducing mechanism in the tumor microenvironment (TME). However, identity of such a mechanism remains elusive. Here, we show that prostaglandin E ₂ (PGE ₂ ) produced in TME directly acts on its receptor EP2/EP4 on Tregs to induce the TI-Treg phenotype. PGE ₂ added to TCR-activated Tregs induces a set of genes, many of which are included in the TI-Treg signature, in both induced Tregs (iTregs) and naturally occurring Tregs (nTregs) via EP2/EP4- cAMP-PKA pathway. Concomitantly, PGE ₂ -treated Tregs exhibit potent suppressive activity to CD8 ⁺ T cells and strongly inhibit their proliferation in an EP4 dependent manner. Consistently, selective loss of EP2 and EP4 in mouse Tregs reduces expression of those genes in Tregs infiltrating Lewis lung carcinoma 1 (LLC1) mouse tumor and significantly delays the tumor progression. In human FOXP3 ⁺ iTregs, PGE ₂ -EP4 signaling upregulated the expression of Treg signature genes, FOXP3, CD25, and CTLA-4 as well as a typical TI-Treg signature gene, 4-1BB, and enhanced suppressive activity. Furthermore, analysis of single-cell RNA sequencing of nasopharyngeal cancer patients demonstrates preferential expression of the TI-Treg signature genes in Tregs infiltrating the PTGS2 ^hi tumor group compared to the PTGS2 ^lo tumor group. These findings suggest that PGE ₂ -EP2/EP4 signaling is one of the core mechanisms inducing the TI-Treg phenotype in TME for tumor growth.

The functional alteration of microglia arises in brains exposed to external stress during early development. Pathophysiological findings of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder suggest cerebellar functional deficits. However, the link between stress-induced microglia reactivity and cerebellar dysfunction is missing. Here, we investigate the developmental immune environment in translational mouse models that combine two risk factors: maternal infection and repeated social defeat stress (2HIT). We find the synergy of inflammatory stress insults, leading to microglial increase specifically in the cerebellum of both sexes. Microglial turnover correlates with the Purkinje neuron loss in 2HIT mice. Highly multiplexed imaging-mass-cytometry identifies a cell transition to TREM2(+) stress-associated microglia in the cerebellum. Single-cell-proteomic clustering reveals IL-6- and TGFβ-signaling association with microglial cell transitions. Reduced excitability of remaining Purkinje cells, cerebellum-involved brain-wide functional dysconnectivity, and behavioral abnormalities indicate cerebellar cognitive dysfunctions in 2HIT animals, which are ameliorated by both systemic and cerebellum-specific microglia replacement.

While prostaglandin E₂ (PGE₂) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by comparative single-cell RNA sequencing of immune cells infiltrating human cancers and syngeneic tumors in female mice. PGE receptors EP4 and EP2 are expressed in lymphocytes and myeloid cells, and their expression is associated with the downregulation of oxidative phosphorylation (OXPHOS) and MYC targets, glycolysis and ribosomal proteins (RPs). Mechanistically, CD8⁺ T cells express EP4 and EP2 upon TCR activation, and PGE₂ blocks IL-2-STAT5 signaling by downregulating Il2ra, which downregulates c-Myc and PGC-1 to decrease OXPHOS, glycolysis, and RPs, impairing migration, expansion, survival, and antitumor activity. Similarly, EP4 and EP2 are induced upon macrophage activation, and PGE₂ downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE₂-EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells.

The functional alteration of microglia emerges in the brains exposed to extrinsic stress insults during early development. Pathophysiological findings of psychiatric disorders such as schizophrenia and autism implied a localized deficit of the cerebellum. However, the link between microglia reactivity and cerebellar dysfunction is missing. Here, we investigated the developmental immune environment of translational mouse models that combine two risk factors: maternal infection and repeated social defeat stress (i.e., 2HIT). We found synergy of inflammatory stress insults produced reactive microglia, specifically in the cerebellum in both sexes. The microglial proliferation correlated with the Purkinje neuron loss in 2HIT mice. Highly multiplexed imaging-mass-cytometry demonstrated a TREM2-positive population of stress-associated microglia in the cerebellum. Single-cell-proteomic clustering revealed IL-6- and TGFβ-signaling association with microglial cell transition. Purkinje cells reduced excitability, cerebellum-involved brain-wide functional dysconnectivity, and behavioral anomalies underpin the cerebellar cognitive dysfunctions in 2HIT animals, ameliorated by cerebellum-specific microglia replacement.

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