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.

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].

INTESTINAL MICROBIOTA IS A MAJOR DETERMINANT IN THE RESPONSE TO ONCOLYTIC VACCINE IN A MOUSE MODEL OF MELANOMA

L. Tripodi
2021

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.
PASTORE, LUCIO
Oncolytic Adenovirus; Gut microbiota; Firmicutes phylum
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
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].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/884815
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