RESUMEN
Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Antibiotic treatment to eradicate A. muciniphila before caloric restriction preserved colonic mucus, whereas A. muciniphila reintroduction restored mucus thinning. Caloric restriction of unirradiated mice raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila in vitro with propionate reduced utilization of mucin as well as of fucose. Treating irradiated mice with an antibiotic targeting A. muciniphila or propionate preserved the mucus layer, suppressed translocation of flagellin, reduced inflammatory cytokines in the colon, and improved thermoregulation. These results suggest that diet, metabolites, and colonic mucus link the microbiome to neutropenic fever and may guide future microbiome-based preventive strategies.
Asunto(s)
Microbioma Gastrointestinal , Trasplante de Células Madre Hematopoyéticas , Neoplasias , Neutropenia , Ratones , Animales , Propionatos , Verrucomicrobia , Moco/metabolismo , Mucinas/metabolismo , Dieta , Neutropenia/metabolismo , Neoplasias/metabolismoRESUMEN
Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.
Asunto(s)
Genómica/métodos , Melanoma/metabolismo , Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN/genética , Humanos , Melanoma/genética , Mutación/genética , Activación Neutrófila/genética , Activación Neutrófila/fisiología , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologíaRESUMEN
In the version of this article originally published, an author was missing from the author list. Alexander J. Lazar should have been included between Jorge M. Blando and James P. Allison. The author has been added to the list, and the author contributions section has been updated to include Alexander J. Lazar's contribution to the study. The error has been corrected in the print, PDF and HTML versions of the manuscript.
RESUMEN
We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
Asunto(s)
Colitis/terapia , Trasplante de Microbiota Fecal/métodos , Microbioma Gastrointestinal/efectos de los fármacos , Ipilimumab/efectos adversos , Anciano , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/uso terapéutico , Colitis/inducido químicamente , Colitis/inmunología , Colitis/microbiología , Femenino , Microbioma Gastrointestinal/inmunología , Humanos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/microbiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/microbiologíaRESUMEN
Clinical evidence is accumulating for a role of the microbiome in contributing to or modulating severity of inflammatory diseases. These studies can be organized by various organ systems involved, as well as type of study approach utilized, whether investigators compared the microbiome of cases versus controls, followed patients longitudinally, or intervened with antibiotics, prebiotics, or bacterial introduction. In this review, we summarize the clinical evidence supporting the microbiome as an important mechanism in the onset and maintenance of inflammation.