The gut microbiota has recently attracted attention as a pathogenic factor in Alzheimer's disease (AD). Microfold (M) cells, which play a crucial role in the gut immune response against external antigens, are also exploited for the entry of pathogenic bacteria and proteins into the body. However, whether changes in M cells can affect the gut environments and consequently change brain pathologies in AD remains unknown.
Five familial AD (5xFAD) and 5xFAD-derived fecal microbiota transplanted (5xFAD-FMT) naïve mice were used to investigate the changes of M cells in the AD environment. Next, to establish the effect of M cell depletion on AD environments, 5xFAD mice and Spib knockout mice were bred, and behavioral and histological analyses were performed when M cell-depleted 5xFAD mice were six or nine months of age.
In this study, we found that M cell numbers were increased in the colons of 5xFAD and 5xFAD-FMT mice compared to those of wild-type (WT) and WT-FMT mice. Moreover, the level of total bacteria infiltrating the colons increased in the AD-mimicked mice. The levels of M cell-related genes and that of infiltrating bacteria showed a significant correlation. The genetic inhibition of M cells (Spib knockout) in 5xFAD mice changed the composition of the gut microbiota, along with decreasing proinflammatory cytokine levels in the colons. M cell depletion ameliorated AD symptoms including amyloid-β accumulation, microglial dysfunction, neuroinflammation, and memory impairment. Similarly, 5xFAD-FMT did not induce AD-like pathologies, such as memory impairment and excessive neuroinflammation in Spib-/- mice.
Therefore, our findings provide evidence that the inhibiting M cells can prevent AD progression, with therapeutic implications.
© 2023. The Author(s).

Tumor-derived extracellular vesicles (TEVs) play crucial roles in mediating immune responses, as they carry and present functional MHC-peptide complexes that enable them to modulate antigen-specific CD8+ T-cell responses. However, the therapeutic potential and immunogenicity of TEV-based therapies against bladder cancer (BC) have not yet been tested. Here, we demonstrated that priming with immunogenic Extracellular Vesicles (EVs) derived from murine MB49 BC cells was sufficient to prevent MB49 tumor growth in mice. Importantly, antibody-mediated CD8+ T-cell depletion diminished the protective effect of MB49 EVs, suggesting that MB49 EVs elicit cytotoxic CD8+ T-cell-mediated protection against MB49 tumor growth. Such antitumor activity may be augmented by TEV-enhanced immune cell infiltration into the tumors. Interestingly, MB49 EV priming was unable to completely prevent, but significantly delayed, unrelated syngeneic murine colon MC-38 tumor growth. Cytokine array analyses revealed that MB49 EVs were enriched with pro-inflammatory factors that might contribute to increasing tumor-infiltrating immune cells in EV-primed MC-38 tumors. These results support the potential application of TEVs in personalized medicine, and open new avenues for the development of adjuvant therapies based on patient-derived EVs aimed at preventing disease progression.

The APOBEC family of cytidine deaminases is one of the most common endogenous sources of mutations in human cancer. Genomic studies of tumors have found that APOBEC mutational signatures are enriched in the HER2 subtype of breast cancer and are associated with immunotherapy response in diverse cancer types. However, the direct consequences of APOBEC mutagenesis on the tumor immune microenvironment have not been thoroughly investigated. To address this, we developed syngeneic murine mammary tumor models with inducible expression of APOBEC3B. We found that APOBEC activity induced antitumor adaptive immune responses and CD4+ T cell-mediated, antigen-specific tumor growth inhibition. Although polyclonal APOBEC tumors had a moderate growth defect, clonal APOBEC tumors were almost completely rejected, suggesting that APOBEC-mediated genetic heterogeneity limits antitumor adaptive immune responses. Consistent with the observed immune infiltration in APOBEC tumors, APOBEC activity sensitized HER2-driven breast tumors to anti-CTLA-4 checkpoint inhibition and led to a complete response to combination anti-CTLA-4 and anti-HER2 therapy. In human breast cancers, the relationship between APOBEC mutagenesis and immunogenicity varied by breast cancer subtype and the frequency of subclonal mutations. This work provides a mechanistic basis for the sensitivity of APOBEC tumors to checkpoint inhibitors and suggests a rationale for using APOBEC mutational signatures and clonality as biomarkers predicting immunotherapy response in HER2-positive (HER2+) breast cancers.
©2021 American Association for Cancer Research.

Despite recent in vivo data demonstrating that high-fat diet (HFD)-induced obesity leads to major perturbations in murine hematopoietic stem cells (HSC), the direct role of a HFD is not yet completely understood. Here, we investigate the direct impact of a short-term HFD on HSC and hematopoiesis in C57BL/6J mice compared with standard diet-fed mice. We detect a loss of half of the most primitive HSC in the bone marrow (BM) cells of HFD-fed mice, which exhibit lower hematopoietic reconstitution potential after transplantation. Impaired maintenance of HSC is due to reduced dormancy after HFD feeding. We discover that a HFD disrupts the TGF-β receptor within lipid rafts, associated to impaired Smad2/3-dependent TGF-β signaling, as the main molecular mechanism of action. Finally, injecting HFD-fed mice with recombinant TGF-β1 avoids the loss of HSC and alteration of the BM's ability to recover, underscoring the fact that a HFD affects TGF-β signaling on HSC.