Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies^{1,2,3,4,5,6,7}. In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage^1,4,8,9. However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2^−/− mice^8,9 and humans with TET2 mutations^1,3,5,6,7, suggesting that extrinsic non-cell-autonomous factors are required for disease onset. Here we show that bacterial translocation and increased interleukin-6 production, resulting from dysfunction of the small-intestinal barrier, are critical for the development of PMP in mice that lack Tet2 expression in haematopoietic cells. Furthermore, in symptom-free Tet2^−/− mice, PMP can be induced by disrupting intestinal barrier integrity, or in response to systemic bacterial stimuli such as the toll-like receptor 2 agonist. PMP was reversed by antibiotic treatment and failed to develop in germ-free Tet2^−/− mice, which illustrates the importance of microbial signals in the development of this condition. Our findings demonstrate the requirement for microbial-dependent inflammation in the development of PMP and provide a mechanistic basis for the variation in PMP penetrance observed in Tet2^−/− mice. This study will prompt new lines of investigation that may profoundly affect the prevention and management of haematopoietic malignancies.

Growing evidence highlights an association between an imbalance in the composition and abundance of bacteria in the breast tissue (referred as microbial dysbiosis) and breast cancer in women. However, studies on the breast tissue microbiome have not been conducted in non-Hispanic Black (NHB) women. We investigated normal and breast cancer tissue microbiota from NHB and non-Hispanic White (NHW) women to identify distinct microbial signatures by race, stage, or tumor subtype. Using 16S rRNA gene sequencing, we observed that phylum Proteobacteria was most abundant in normal (n = 8), normal adjacent to tumor (normal pairs, n = 11), and breast tumors from NHB and NHW women (n = 64), with fewer Firmicutes, Bacteroidetes, and Actinobacteria. Breast tissues from NHB women had a higher abundance of genus Ralstonia compared to NHW tumors, which could explain a portion of the breast cancer racial disparities. Analysis of tumor subtype revealed enrichment of family Streptococcaceae in TNBC. A higher abundance of genus Bosea (phylum Proteobacteria) increased with stage. This is the first study to identify racial differences in the breast tissue microbiota between NHB and NHW women. Further studies on the breast cancer microbiome are necessary to help us understand risk, underlying mechanisms, and identify potential microbial targets.

Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown. In lean and obese mice, tumor progression and immune reprogramming were quantified in BC tumors treated with anti-programmed death-1 (PD-1) or control. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. BC primes systemic immunity to be highly responsive to obesity, leading to greater immunosuppression, which may explain greater anti-PD-1 efficacy. Anti-PD-1 significantly reinvigorates antitumor immunity despite persistent obesity. Laminin subunit beta-2 (Lamb2), downregulated by anti-PD-1, significantly predicts patient survival. Lastly, a microbial signature associated with anti-PD-1 efficacy is identified. Thus, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity. VIDEO

As an active interface between the host and their diet, the gut microbiota influences host metabolic adaptation; however, the contributions of fungi have been overlooked. Here, we investigate whether variations in gut mycobiome abundance and composition correlate with key features of host metabolism. We obtained animals from four commercial sources in parallel to test if differing starting mycobiomes can shape host adaptation in response to processed diets. We show that the gut mycobiome of healthy mice is shaped by the environment, including diet, and significantly correlates with metabolic outcomes. We demonstrate that exposure to processed diet leads to persistent differences in fungal communities that significantly associate with differential deposition of body mass in male mice compared to mice fed standardized diet. Fat deposition in the liver, transcriptional adaptation of metabolically active tissues and serum metabolic biomarker levels are linked with alterations in fungal community diversity and composition. Specifically, variation in fungi from the generaThermomycesandSaccharomycesmost strongly associate with metabolic disturbance and weight gain. These data suggest that host–microbe metabolic interactions may be influenced by variability in the mycobiome. This work highlights the potential significance of the gut mycobiome in health and has implications for human and experimental metabolic studies.