No abstract

Oral vancomycin treatment enhances the direct and abscopal antitumor effects of hypofractionated RT in preclinical melanoma and lung/cervical tumor models. Given the role of the gut microbiota in modulating immune cells that are also known to be involved in the response to RT, we examined whether the microbiota-regulated systemic immune response contributes to the RT-mediated anticancer immune response. The effects of oral vancomycin treatment are localized and impact the gut microbiota directly without any known systemic effects (21-23). Vancomycin (mostly targeting gram-positive bacteria) or a neomycin/metronidazole (Neo/Met) regimen (mostly targeting gram-negative bacteria

Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota.

Munro’s microabscesses contain polymorphonuclear leukocytes and form specifically in the epidermis of psoriasis patients. The mechanism whereby the neutrophils are recruited into the epidermis is poorly understood. Using a combination of human and mouse primary keratinocyte cell cultures and the imiquimod-induced psoriasis-like mouse model of skin inflammation we explored the role of interleukin-1 (IL-1) signaling in microabscess formation. In vitro imiquimod stimulated production of IL-1α and neutrophil recruiting chemokines. Imiquimod activated chemokine expression was dependent upon adenosine signaling and independent of IL-1α and IL-1 receptor type 1 (IL-1R1); nevertheless, IL-1α could enhance chemokine expression initiated by imiquimod. Topical application of imiquimod in vivo led to epidermal microabscess formation, acanthosis and increased IL-1α and chemokine expression in the skin of wild type mice. However, in IL-1R1 deficient mice these responses were either absent or dramatically reduced. These results demonstrate that IL-1α and IL-1R1 signaling is essential for microabscess formation, neutrophil recruiting chemokine expression and acanthosis in psoriasis-like skin inflammation induced by imiquimod.