Synergistic anti-tumor efficacy of oncolytic influenza viruses and B7-H3 immune- checkpoint inhibitors against IC-resistant lung cancers

Non-small cell lung cancers (NSCLCs) establish a highly immunosuppressive tumor microenvironment supporting cancer growth. To interfere with cancer-mediated immunosuppression, selective immune-checkpoint inhibitors (ICIs) have been approved as a standard-of-care treatment for NSCLCs. However, the ma...

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Main Authors: Dörthe Masemann, Ramona Meissner, Tanja Schied, Brian D Lichty, Ulf R Rapp, Viktor Wixler, Stephan Ludwig
Format: Article
Language:English
Published: Taylor & Francis Group 2021-01-01
Series:OncoImmunology
Subjects:
Online Access:http://dx.doi.org/10.1080/2162402X.2021.1885778
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spelling doaj-a9f07968906048c0afdd69db5a8832132021-03-02T13:49:51ZengTaylor & Francis GroupOncoImmunology2162-402X2021-01-0110110.1080/2162402X.2021.18857781885778Synergistic anti-tumor efficacy of oncolytic influenza viruses and B7-H3 immune- checkpoint inhibitors against IC-resistant lung cancersDörthe Masemann0Ramona Meissner1Tanja Schied2Brian D Lichty3Ulf R Rapp4Viktor Wixler5Stephan Ludwig6University of MuensterUniversity of MuensterInstitute of Virology, University of MuensterMcMaster University, HamiltonMax Planck Institute for Heart and Lung ResearchUniversity of MuensterUniversity of MuensterNon-small cell lung cancers (NSCLCs) establish a highly immunosuppressive tumor microenvironment supporting cancer growth. To interfere with cancer-mediated immunosuppression, selective immune-checkpoint inhibitors (ICIs) have been approved as a standard-of-care treatment for NSCLCs. However, the majority of patients poorly respond to ICI-based immunotherapies. Oncolytic viruses are amongst the many promising immunomodulatory treatments tested as standalone therapy or in combination with ICIs to improve therapeutic outcome. Previously, we demonstrated the oncolytic and immunomodulatory efficacy of low-pathogenic influenza Aviruses (IAVs) against NSCLCs in immunocompetent transgenic mice with alung-specific overexpression of active Raf kinase (Raf-BxB). IAV infection not only resulted in significant primary virus-induced oncolysis, but also caused afunctional reversion of tumor-associated macrophages (TAMs) comprising additional anti-cancer activity. Here we show that NSCLCs as well as TAMs and cytotoxic immune cells overexpress IC molecules of the PD-L2/PD-1 and B7-H3 signaling axes. Thus, we aimed to combine oncolytic IAV-infection with ICIs to exploit the benefits of both anti-cancer approaches. Strikingly, IAV infection combined with the novel B7-H3 ICI led to increased levels of M1-polarized alveolar macrophages and increased lung infiltration by cytotoxic Tlymphocytes, which finally resulted in significantly improved oncolysis of about 80% of existing tumors. In contrast, application of clinically approved α-PD-1 IC antibodies alone or in combination with oncolytic IAV did not provide additional oncolytic or immunomodulatory efficacy. Thus, individualized therapy with synergistically acting oncolytic IAV and B7-H3 ICI might be an innovative future approach to target NSCLCs that are resistant to approved ICIs in patients.http://dx.doi.org/10.1080/2162402X.2021.1885778lung canceroncolytic virusimmune-checkpoint inhibitorcancer immunosuppressionimmunotherapy
collection DOAJ
language English
format Article
sources DOAJ
author Dörthe Masemann
Ramona Meissner
Tanja Schied
Brian D Lichty
Ulf R Rapp
Viktor Wixler
Stephan Ludwig
spellingShingle Dörthe Masemann
Ramona Meissner
Tanja Schied
Brian D Lichty
Ulf R Rapp
Viktor Wixler
Stephan Ludwig
Synergistic anti-tumor efficacy of oncolytic influenza viruses and B7-H3 immune- checkpoint inhibitors against IC-resistant lung cancers
OncoImmunology
lung cancer
oncolytic virus
immune-checkpoint inhibitor
cancer immunosuppression
immunotherapy
author_facet Dörthe Masemann
Ramona Meissner
Tanja Schied
Brian D Lichty
Ulf R Rapp
Viktor Wixler
Stephan Ludwig
author_sort Dörthe Masemann
title Synergistic anti-tumor efficacy of oncolytic influenza viruses and B7-H3 immune- checkpoint inhibitors against IC-resistant lung cancers
title_short Synergistic anti-tumor efficacy of oncolytic influenza viruses and B7-H3 immune- checkpoint inhibitors against IC-resistant lung cancers
title_full Synergistic anti-tumor efficacy of oncolytic influenza viruses and B7-H3 immune- checkpoint inhibitors against IC-resistant lung cancers
title_fullStr Synergistic anti-tumor efficacy of oncolytic influenza viruses and B7-H3 immune- checkpoint inhibitors against IC-resistant lung cancers
title_full_unstemmed Synergistic anti-tumor efficacy of oncolytic influenza viruses and B7-H3 immune- checkpoint inhibitors against IC-resistant lung cancers
title_sort synergistic anti-tumor efficacy of oncolytic influenza viruses and b7-h3 immune- checkpoint inhibitors against ic-resistant lung cancers
publisher Taylor & Francis Group
series OncoImmunology
issn 2162-402X
publishDate 2021-01-01
description Non-small cell lung cancers (NSCLCs) establish a highly immunosuppressive tumor microenvironment supporting cancer growth. To interfere with cancer-mediated immunosuppression, selective immune-checkpoint inhibitors (ICIs) have been approved as a standard-of-care treatment for NSCLCs. However, the majority of patients poorly respond to ICI-based immunotherapies. Oncolytic viruses are amongst the many promising immunomodulatory treatments tested as standalone therapy or in combination with ICIs to improve therapeutic outcome. Previously, we demonstrated the oncolytic and immunomodulatory efficacy of low-pathogenic influenza Aviruses (IAVs) against NSCLCs in immunocompetent transgenic mice with alung-specific overexpression of active Raf kinase (Raf-BxB). IAV infection not only resulted in significant primary virus-induced oncolysis, but also caused afunctional reversion of tumor-associated macrophages (TAMs) comprising additional anti-cancer activity. Here we show that NSCLCs as well as TAMs and cytotoxic immune cells overexpress IC molecules of the PD-L2/PD-1 and B7-H3 signaling axes. Thus, we aimed to combine oncolytic IAV-infection with ICIs to exploit the benefits of both anti-cancer approaches. Strikingly, IAV infection combined with the novel B7-H3 ICI led to increased levels of M1-polarized alveolar macrophages and increased lung infiltration by cytotoxic Tlymphocytes, which finally resulted in significantly improved oncolysis of about 80% of existing tumors. In contrast, application of clinically approved α-PD-1 IC antibodies alone or in combination with oncolytic IAV did not provide additional oncolytic or immunomodulatory efficacy. Thus, individualized therapy with synergistically acting oncolytic IAV and B7-H3 ICI might be an innovative future approach to target NSCLCs that are resistant to approved ICIs in patients.
topic lung cancer
oncolytic virus
immune-checkpoint inhibitor
cancer immunosuppression
immunotherapy
url http://dx.doi.org/10.1080/2162402X.2021.1885778
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