Gut microflora affect local and systemic inflammatory responses, and inflammation is involved in both pathogenesis and treatment of cancers, but it is unclear whether gut microflora affect inflammation in the sterile tumor microenvironment. In a study reported in Science, Iida and colleagues assessed whether disruption of commensal gut flora in mice had an effect on response to immunotherapy or chemotherapy in tumor models.
In the study, mice received antibiotic treatment for 3 weeks before subcutaneous tumor inoculation and continuously throughout the studies. EL4 lymphoma, MC38 colon cancer, or B16 melanoma tumors were grown to ≥ 4 mm prior to immunotherapy with CpG-oligonucleotide plus anti–interleukin 10 receptor antibody or chemotherapy with oxaliplatin or cisplatin.
Gene-expression analysis of MC38 and EL4 tumors prior to anticancer therapy showed downregulation of genes involved in inflammation, phagocytosis, antigen presentation, and adaptive immune responses and upregulation of genes involved in tissue development, cancer, and metabolism in antibiotic-treated mice. Levels of bacteria were restored to pretreatment levels 1 week after stopping antibiotics, and bacterial diversity and composition gradually increased but did not reach pre-antibiotic levels.
In antibiotic-treated or germ-free mice, tumor-infiltrating myeloid-derived cells had a blunted response to immunotherapy in mice with MC38 and B16 tumors, with antibiotic-treated mice having reduced tumor necrosis and reduced survival compared with control mice. Antibiotic-treated and germ-free mice with EL4 or MC38 tumors had reduced tumor regression and survival compared with control mice receiving platinum therapy, with the antibiotic-treated mice exhibiting reduced production of reactive oxygen species and cytotoxicity. Gene-expression analysis showed that induction of proinflammatory genes was decreased in the absence of microbiota after oxaliplatin treatment, indicating that inflammation was essential to the antitumor effect of the drug.
The investigators concluded:
[O] ptimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.