Human microbiota influence the immune cell composition and gene expression in the tumor environment of a murine model of glioma.

in Gut microbes by George B H Green, Alexis N Cox-Holmes, Gillian H Marlow, Anna Claire E Potier, Yong Wang, Lianna Zhou, Dongquan Chen, Casey D Morrow, Braden C McFarland

TLDR

  • The study finds that human microbiota influences immune cell infiltration and gene expression in a murine glioma model, with implications for immunotherapy approaches.

Abstract

Immunotherapy has shown success against other cancers but not glioblastoma. Previous data has revealed that microbiota influences anti-PD-1 efficacy. We have previously found that, when using gnotobiotic mice transplanted with human fecal microbiota, the gut microbial composition influenced the response to anti-PD-1 in a mouse model of glioma. However, the role of the human microbiota in influencing the mouse immune cells in the glioma microenvironment and anti-PD-1 response was largely unknown. Using two distinct humanized microbiome (HuM) lines, we used single-cell RNA sequencing (scRNA-seq) to determine how gut microbiota affect immune infiltration and gene expression in a murine glioma model. 16S rRNA sequencing was performed on fecal samples from HuM1 (H1) and HuM2 (H2) mice. Mice were intracranially injected with murine glioma cells (GL261), and on day 13 treated with one dose of isotype control or anti-PD1. Mice were euthanized on day 14 for analysis of all immune cells in the tumors by scRNA-seq. HuM1 and HuM2 mice had different microbial populations, with HuM1 being primarily dominated via, and HuM2 being primarily composed of. Sc-RNA-seq of the tumor immune cells revealed 21 clusters with significant differences between H1 and H2 samples with a larger population of M1 type macrophages in H1 samples. Gene expression analysis revealed higher expression of inflammatory markers in the M1 population in H2 mice treated with anti-PD-1. Microbial gut communities influence the presence and gene activation patterns of immune cells in the brain tumors of mice both under control (isotype) and following anti-PD-1 treatment.

Overview

  • The study focuses on analyzing the role of human microbiota in influencing the immune response and anti-PD-1 efficacy in a murine glioma model.
  • The study uses two distinct humanized microbiome (HuM) lines, HuM1 and HuM2, which have different microbial populations.
  • The primary objective of the study is to determine how gut microbiota affect immune infiltration and gene expression in a murine glioma model, particularly under anti-PD-1 treatment.

Comparative Analysis & Findings

  • The study found significant differences in the microbial populations of HuM1 and HuM2 mice, with HuM1 primarily dominated by and HuM2 primarily composed of.
  • Single-cell RNA sequencing (scRNA-seq) analysis revealed 21 clusters with significant differences between HuM1 and HuM2 samples.
  • The study found a larger population of M1 type macrophages in HuM1 samples, and higher expression of inflammatory markers in the M1 population in HuM2 mice treated with anti-PD-1.

Implications and Future Directions

  • The findings suggest that human microbiota influences the presence and gene activation patterns of immune cells in the brain tumors of mice, both under control and following anti-PD-1 treatment.
  • The study highlights the importance of considering the role of microbiota in immunotherapy trials, particularly for glioblastoma.
  • Future studies could investigate the mechanisms by which microbiota influence immune cell activation and response to anti-PD-1 therapy in a murine glioma model.
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