DISSECTING THE STING-DEPENDENT MOLECULAR MECHANISMS IN A PRECLINICAL MODEL OF COMBINED TREATMENT WITH TUMOUR-TARGETED HERPES SIMPLEX VIRUS AND IMMUNE CHECKPOINT BLOCKADE
Tesi di Dottorato
Data di Pubblicazione:
2021
Citazione:
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].
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.
Tipologia IRIS:
Tesi di dottorato
Keywords:
Herpes simplex; HSV-1; oncolytic virus; immunogenic cell death; STING Knockout; RNA profiling; TMEM173
Elenco autori:
G. Froechlich
Link alla scheda completa: