Gut microbiota alterations affect glioma growth and innate immune cells involved in tumor immunosurveillance in mice

Abstract

Glioma is a CNS tumor with few therapeutic options. Recently, host microbiota has been involved in the immune modulation of different tumors, but no data are available on the possible effects of the gut-immune axis on brain tumors. Here, we investigated the effect of gut microbiota alteration in a syngeneic (GL261) mouse model of glioma, treating mice with two antibiotics (ABX) and evaluating the effects on tumor growth, microbe composition, natural killer (NK) cells and microglia phenotype. We report that ABX treatment (i) altered the intestinal microbiota at family level, (ii) reduced cytotoxic NK cell subsets, and (iii) altered the expression of inflammatory and homeostatic proteins in microglia. All these findings could contribute to the increased growth of intracranial glioma that was observed after ABX treatment. These results demonstrate that chronic ABX administration alters microbiota composition and contributes to modulate brain immune state paving the way to glioma growth.of innate immune cells such as microglia and monocytes, which account to about 30% of the whole tumor mass and whose presence negatively correlates with patient's survival [3]. The panel of infiltrating immune cells also comprises T lymphocytes and natural killer (NK) cells [4,5]. NK cells have direct cytotoxic activity against cancer cells [6], and their depletion hampers the * Both authors contributed equally to this work.

Hallmarks of cancer—the new testament

“…We argue that it has a role in each of the triumvirate of immunoediting [ 150 ], namely elimination, equilibrium and escape during tumourigenesis and as such is a pivotal enabling hallmark of cancer. Antibiotic mediated alteration of gut microbiota has been shown to alter the cerebral tumour microenvironment, thus affecting glioma progression [ 151 ], which bring us to our final enabling hallmark of cancer—nerves/neuronal signalling.…”

Human gut microbial communities dictate efficacy of anti-PD-1 therapy in a humanized microbiome mouse model of glioma

“… 29 Lastly, a recent paper by D’Alessandro et al, found that administering antibiotics altered the microbiome of mice, reduced the percentage of cytotoxic cells NK (CD27 + CD11b + ) leading to an increase in glioma size, with no difference in the frequency of infiltrating lymphocytes (CD45 + CD3 + T-cells). 37 All of these reports indicate how complicated the role of the microbiome is in tumor immune interactions. In a preliminary experiment, we have found that the presence of microbes in HuM2 mice is required for the positive effect of anti-PD-1 ( Supplementary Figure 3 ).…”

New Insights Into the Cancer–Microbiome–Immune Axis: Decrypting a Decade of Discoveries

“…It has been demonstrated that specific bacterial species in human colon cancer biopsies correlate with prognostically favorable increase in T cell infiltration by virtue of increased expression of T cell recruiting chemokines by the cancer cells ( Lachnospiraceae and Ruminococcaceae ) and increased chemokine receptor expression on multiple T cell subsets ( Methylobacteriaceae ) ( 117 ). Preliminary findings from a preclinical glioma model suggest that treatment of tumor bearing mice with vancomycin plus gentamicin decreased gut microbial diversity, decreased infiltration of CD27 + CD11b + cytotoxic NK cells and led to increased tumor burden ( 25 ). Another specific interaction in seen is the form of molecular mimicry, where microbial epitopes can mimic tumor antigens, leading to enhanced anti-tumor immunity through generation of microbial epitope specific activated CD8 + T cells (discussed later) ( 118 ).…”