Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in male APPPS1-21 AD model mice. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (abx) and identified a significant increase in plasma propionate, a gut-derived short chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the abx-induced phenotype. Astrocyte-specific RNA sequencing on abx and propionate treated mice showed reduced expression of pro-inflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments where we found abx and propionate decreased peripheral RAR-related orphan receptor-γ (Rorγt)+ CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Lastly, using an IL-17 monoclonal antibody to deplete IL-17, we found that propionate reduces reactive astrocytosis and Aβ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for AD.

Immune checkpoint-based immunotherapy has shown limited efficacy in the treatment of ovarian cancer. In recent years, the emergence of immune checkpoint co-targeting therapies, led by the combination targeting of TIGIT and FAK, has shown promise in ovarian cancer treatment. Our preliminary research indicates that TIGIT is predominantly expressed in regulatory T cells during ovarian cancer. However, the therapeutic impact of TIGIT targeting based on regulatory T cells in ovarian cancer remains to be elucidated. We utilized ID8 cells to establish a mouse model of ovarian cancer. Through flow cytometry and co-culture methods, we validated the relationship between the functionality of regulatory T cells and tumor masses, and confirmed the crucial role of TIGIT in immune suppression in ovarian cancer. Furthermore, using Foxp3-diphtheria toxin receptor (DTR) mice, we substantiated that the combined TIGIT antibody treatment, based on targeting regulatory T cells, effectively slowed down the progression of ovarian cancer. Taken together, our results have demonstrated that dual targeting of regulatory T cells and TIGIT effectively retards tumor growth, laying the groundwork for the clinical application of immune checkpoint combination therapies. Future research in ovarian cancer immunotherapy is leaning towards a strategy that combines multiple targets, and specific cell-type immunotherapies.
© 2024. The Author(s).

Reprogramming tryptophan metabolism (TRP) may be able to overcome immunosuppression and restore the immune checkpoint blockade (ICB) response in patients with epithelial ovarian cancer (EOC) resistant to ICB therapy because TRP metabolism is involved in the kynurenine/indole and serotonin pathways of tryptophan metabolism. Herein, employing amitriptyline (AMI), an antagonist of TLR4 and serotonin transporter (SERT), we revealed that AMI remodels the immunological landscape of EOC. In particular, AMI lowered the expression of IDO1, IL-4I1, and PD-L1, the quantity of KYN and indoles, and the level of immunosuppressive immune cells MDSC, Tregs, and CD8+CD39+/PD-1+ T cell. AMI boosted the killing potential of anti-PD-1-directed CD8+T cells and worked in concert with PD-1 inhibitors to suppress tumor growth and to prolong the survival of EOC-bearing mice. This work highlights AMI as an effective regulator of ICB response by manipulating EOC cell TRP metabolism, indicating it could be a potential strategy for improving EOC ICB therapy.
© 2024 The Author(s).

Super enhancers (SEs) are large clusters of transcriptional enhancers driving the expression of genes crucial for defining cell identity. In cancer, tumor-specific SEs activate key oncogenes, leading to tumorigenesis. Identifying SE-driven oncogenes in tumors and understanding their functional mechanisms is of significant importance. In this study, a previously unreported SE region is identified in T-cell acute lymphoblastic leukemia (T-ALL) patient samples and cell lines. This SE activates the expression of interferon regulatory factor 2 binding protein 2 (IRF2BP2) and is regulated by T-ALL master transcription factors (TFs) such as ETS transcription factor ERG (ERG), E74 like ETS transcription factor 1 (ELF1), and ETS proto-oncogene 1, transcription factor (ETS1). Hematopoietic system-specific IRF2BP2 conditional knockout mice is generated and showed that IRF2BP2 has minimal impact on normal T cell development. However, in vitro and in vivo experiments demonstrated that IRF2BP2 is crucial for T-ALL cell growth and survival. Loss of IRF2BP2 affects the MYC and E2F pathways in T-ALL cells. Cleavage under targets and tagmentation (CUT&Tag) assays and immunoprecipitation revealed that IRF2BP2 cooperates with the master TFs of T-ALL cells, targeting the enhancer of the T-ALL susceptibility gene recombination activating 1 (RAG1) and modulating its expression. These findings provide new insights into the regulatory network within T-ALL cells, identifying potential new targets for therapeutic intervention.
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

The efficacy and side effects of radiotherapy (RT) depend on parameters like dose and the volume of irradiated tissue. RT induces modulations of the tumor immune microenvironment (TIME) that are dependent on the dose. Low dose RT (LDRT, i.e., single doses of 0.5-2 Gy) has been shown to promote immune infiltration into the tumor. Here we hypothesize that partial tumor irradiation combining the immunostimulatory/non-lethal properties of LDRT with cell killing/shrinkage properties of high dose RT (HDRT) within the same tumor mass could enhance anti-tumor responses when combined with immunomodulators. In models of colorectal and breast cancer in immunocompetent female mice, partial irradiation (PI) with millimetric precision to deliver LDRT (2 Gy) and HDRT (16 Gy) within the same tumor induces substantial tumor control when combined with anti-PD1. Using flow cytometry, cytokine profiling and single-cell RNA sequencing, we identify a crosstalk between the TIME of the differentially irradiated tumor volumes. PI reshapes tumor-infiltrating CD8+ T cells into more cytotoxic and interferon-activated phenotypes but also increases the infiltration of pro-tumor neutrophils driven by CXCR2. The combination of the CXCR2 antagonist SB225002 with PD1 blockade and PI improves tumor control and mouse survival. Our results suggest a strategy to reduce RT toxicity and improve the therapeutic index of RT and immune checkpoint combinations.
© 2024. The Author(s).