Gut Microbiota Promotes Tumor Growth in Mice by Modulating Immune Response

Abstract

We studied the effects of gut microbiome depletion by oral antibiotics on tumor growth in subcutaneous and liver metastases models of pancreatic cancer, colon cancer, and melanoma. Gut microbiome depletion significantly reduced tumor burden in all the models tested. However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells. Flow cytometry analyses demonstrated that gut microbiome depletion led to significant increase in interferon gamma-producing T cells with corresponding decrease in interleukin 17A and interleukin 10-producing T cells. Our results suggest that gut microbiome modulation could emerge as a novel immunotherapeutic strategy.

Keywords: Gut Bacteria; Immune Regulation; Metastases; Tumor Promotion.

Figure 1. Depletion of gut microbiome decreases tumor burden in multiple models of cancer

(A) schematic of the experiments; (B) & (C) saline and antibiotics-gavaged C57BL/6J mice were subcutaneously implanted with (B) KPC pancreatic cancer cells (n=13 for saline; 7 for antibiotics) or (C) Braf-Pten melanoma cells (n=14 for saline; 15 for antibiotics). Experiments were repeated four independent times with similar results. Results from one experiment are shown. X-axis label in (B) and (C) tumor kinetics represents days after tumor injection. (D) & (E) saline and antibiotics-gavaged mice were injected intrasplenically with (D) KPC cells (n=9 for saline; 7 for antibiotics) or (E) B16-F10 melanoma cells (n=10 for saline; 9 for antibiotics) (Unpaired Student's t-test with Welch's correction was used. Data is shown as mean±SEM; *, P<0.05; **, P<0.01; ***, P<0.005; ****, P<0.0005)

Figure 2. Gut microbiome depletion modulates tumor immune-environment

(A) C57BL/6J mice carrying a Rag1^tm1Mom mutation were given saline or oral antibiotics and were subcutaneously implanted with KPC cells (n=10 for saline; 9 for antibiotics). X-axis label in tumor kinetics represents days after tumor injection; (B)–(F) KPC cells were subcutaneously implanted in wildtype mice and tumors were immunophenotyped by flowcytometry (n=9 for saline; 6 for antibiotics). Histograms depict individual representative samples. (G) Saline or antibiotics-treated KPC-bearing mice were either injected with anti-IL17a or isotype. (n=9 for saline+isotype, 8 for antibiotics+isotype, 10 for saline+anti-IL17a, 11 for antibiotics+anti-IL17a group) (Unpaired Student's t-test with Welch's correction was used. Data is shown as mean±SEM; *, P<0.05; ***, P<0.005).