INTESTINAL MICROBIOTA IS A MAJOR DETERMINANT IN THE RESPONSE TO ONCOLYTIC VACCINE IN A MOUSE MODEL OF MELANOMA
Tesi di Dottorato
Data di Pubblicazione:
2021
Citazione:
INTESTINAL MICROBIOTA IS A MAJOR DETERMINANT IN THE RESPONSE TO ONCOLYTIC VACCINE IN A MOUSE MODEL OF MELANOMA / L. Tripodi ; supervisor: L. Pastore ; internal advisor: F. Salvatore ; external advisor: V. Cerullo ; co-tutor: M. Zollo. Università degli Studi di Milano, 2021 Dec 13. 33. ciclo, Anno Accademico 2021. [10.13130/tripodi-lorella_phd2021-12-13].
Abstract:
Cancer immunotherapy has achieved tremendous results, however the outcome of therapies
targeting immune inhibitory pathways, specifically CTLA-4 and the axis between programmed cell
death protein 1 (PD-1) and its ligand 1 (PD-L1) has many genetic and environmental sources of
variability. Many studies demonstrated the influence of gut microbiome on immune checkpoint
inhibitors (ICIs) outcome. Besides ICIs, oncolytic vaccines (OVs) are a promising therapeutic
alternative in cancer immunotherapy with possible relevant contribution to treatment of several
types of tumors; OVs are, in fact, able to convert immunologically “cold” tumors into “hot” ones.
OVs represent an optimum candidate to combine with ICIs, increasing their response blockade both
in immunogenic and poorly immunogenic tumors. We hypothesized that manipulation of intestinal
gut microbiota could also affect OVs therapeutic efficacy; at this aim, we determined whether
efficacy of the oncolytic adenovirus Ad5D24-CpG (Ad-CpG) therapy could be affected by the gut
microbiome in a syngeneic mouse model of melanoma. Sterilization of the gut microbiota with highdose vancomycin impaired efficacy of Ad-CpG therapy, reducing the tumor-infiltrating IFN-gamma
CD8 T-cell. Cohousing mice pre-treated with vancomycin and a control group, with consequent
microbiota restoration, prior to treatment with Ad-CpG, ablated the negative effect of antibiotic,
confirming that Ad-CpG-reduced efficacy was mediated by the intestinal microbiota.
Considering the ability of Bifidobacterium as a positive regulator of antitumor immunity in vivo, by
promoting pro-inflammatory signals in innate immune cells, we evaluated tumor regression in
syngeneic mouse model of melanoma treated with a combination of Ad-CpG and Bifidobacterium
spp. cocktail. The group receiving the combined regimen showed the best tumor control and an
enrichment of bacteria belong to Firmicutes phylum, evaluated by fecal microbiome profiling by 16S
rRNA. Our data indicates that gut microbiota affects the immune responses elicited by oncolytic
adenovirus Ad-CpG and Bifidobacterium supplementations maximize its activity.
Tipologia IRIS:
Tesi di dottorato
Keywords:
Oncolytic Adenovirus; Gut microbiota; Firmicutes phylum
Elenco autori:
L. Tripodi
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