Oncolytic viruses promote anti-tumour immune response by direct tumour cell killing and activation of intratumoural immune system. The role of innate antiviral immune response to oncolytic viruses is still debated, as they counteract viral replication and trigger adaptive antitumor immunity. The DNA sensing-mediated cGAS/STING axis may act as a key balancer between lytic and immunotherapeutic activity of oncolytic viruses. Indeed, upon infection, viral DNA is sensed by cGAS/STING axis that, in turn, induces type-I interferon cascade counteracting viral replication and spread. For this reason, STING represents a hurdle for classical lytic-centric function of oncolytic viruses. On the other side, the immunological role of STING should also be considered, as it is emerging as a key bridge between innate and adaptive immunity. To evaluate the role of STING expression in tumour cells in response to onco-virotherapy, we generated murine STING KO tumour cell lines through CRISPR/Cas9 genome editing. Preclinical studies in syngeneic immunocompetent tumour-bearing mice showed that the inactivation of STING in tumour cells, while favouring oncolytic viral replication, impaired the immunotherapeutic effects of combination therapy based on herpetic oncolytic virus and PD1 blockade. Molecular characterization of tumours revealed that loss of STING prevents antitumour immune activation inducing a tolerogenic cell death and immunosuppressive tumour microenvironment. Accordingly, I propose that antiviral, tumourresident STING provides fundamental contributions to heat-up the TME eliciting immunotherapeutic efficacy of oncolytic viruses.

DISSECTING THE STING-DEPENDENT MOLECULAR MECHANISMS IN A PRECLINICAL MODEL OF COMBINED TREATMENT WITH TUMOUR-TARGETED HERPES SIMPLEX VIRUS AND IMMUNE CHECKPOINT BLOCKADE / G. Froechlich ; tutor: N. Zambrano; co-tutor: M. Zollo; advisor interno: A. Iolascon ; advisor esterno: F. Grassi. - : . Università degli Studi di Milano, 2021 Dec 13. ((33. ciclo, Anno Accademico 2021. [10.13130/froechlich-guendalina_phd2021-12-13].

DISSECTING THE STING-DEPENDENT MOLECULAR MECHANISMS IN A PRECLINICAL MODEL OF COMBINED TREATMENT WITH TUMOUR-TARGETED HERPES SIMPLEX VIRUS AND IMMUNE CHECKPOINT BLOCKADE

G. Froechlich
2021

Abstract

Oncolytic viruses promote anti-tumour immune response by direct tumour cell killing and activation of intratumoural immune system. The role of innate antiviral immune response to oncolytic viruses is still debated, as they counteract viral replication and trigger adaptive antitumor immunity. The DNA sensing-mediated cGAS/STING axis may act as a key balancer between lytic and immunotherapeutic activity of oncolytic viruses. Indeed, upon infection, viral DNA is sensed by cGAS/STING axis that, in turn, induces type-I interferon cascade counteracting viral replication and spread. For this reason, STING represents a hurdle for classical lytic-centric function of oncolytic viruses. On the other side, the immunological role of STING should also be considered, as it is emerging as a key bridge between innate and adaptive immunity. To evaluate the role of STING expression in tumour cells in response to onco-virotherapy, we generated murine STING KO tumour cell lines through CRISPR/Cas9 genome editing. Preclinical studies in syngeneic immunocompetent tumour-bearing mice showed that the inactivation of STING in tumour cells, while favouring oncolytic viral replication, impaired the immunotherapeutic effects of combination therapy based on herpetic oncolytic virus and PD1 blockade. Molecular characterization of tumours revealed that loss of STING prevents antitumour immune activation inducing a tolerogenic cell death and immunosuppressive tumour microenvironment. Accordingly, I propose that antiviral, tumourresident STING provides fundamental contributions to heat-up the TME eliciting immunotherapeutic efficacy of oncolytic viruses.
ZAMBRANO, NICOLA
Herpes simplex; HSV-1; oncolytic virus; immunogenic cell death; STING Knockout; RNA profiling; TMEM173
Settore BIO/11 - Biologia Molecolare
DISSECTING THE STING-DEPENDENT MOLECULAR MECHANISMS IN A PRECLINICAL MODEL OF COMBINED TREATMENT WITH TUMOUR-TARGETED HERPES SIMPLEX VIRUS AND IMMUNE CHECKPOINT BLOCKADE / G. Froechlich ; tutor: N. Zambrano; co-tutor: M. Zollo; advisor interno: A. Iolascon ; advisor esterno: F. Grassi. - : . Università degli Studi di Milano, 2021 Dec 13. ((33. ciclo, Anno Accademico 2021. [10.13130/froechlich-guendalina_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/2434/883382
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