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Cited by 186

The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.

Viral Infection of Tumors Overcomes Resistance to PD-1-immunotherapy by Broadening Neoantigenome-directed T-cell Responses

Open access
Woller, Norman, Gürlevik, Engin, Fleischmann-Mundt, Bettina, Schumacher, Anja, Knocke, Sarah, Kloos, Arnold M, Saborowski, Michael, Geffers, Robert, Manns, Michael P, Wirth, Thomas C, Kubicka, Stefan, Kühnel, Florian·2015·Molecular Therapy
DOI 10.1038/mt.2015.115
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Abstract

There is evidence that viral oncolysis is synergistic with immune checkpoint inhibition in cancer therapy but the underlying mechanisms are unclear. Here, we investigated whether local viral infection of malignant tumors is capable of overcoming systemic resistance to PD-1-immunotherapy by modulating the spectrum of tumor-directed CD8 T-cells. To focus on neoantigen-specific CD8 T-cell responses, we performed transcriptomic sequencing of PD-1-resistant CMT64 lung adenocarcinoma cells followed by algorithm-based neoepitope prediction. Investigations on neoepitope-specific T-cell responses in tumor-bearing mice demonstrated that PD-1 immunotherapy was insufficient whereas viral oncolysis elicited cytotoxic T-cell responses to a conserved panel of neoepitopes. After combined treatment, we observed that PD-1-blockade did not affect the magnitude of oncolysis-mediated antitumoral immune responses but a broader spectrum of T-cell responses including additional neoepitopes was observed. Oncolysis of the primary tumor significantly abrogated systemic resistance to PD-1-immunotherapy leading to improved elimination of disseminated lung tumors. Our observations were confirmed in a transgenic murine model of liver cancer where viral oncolysis strongly induced PD-L1 expression in primary liver tumors and lung metastasis. Furthermore, we demonstrated that combined treatment completely inhibited dissemination in a CD8 T-cell-dependent manner. Therefore, our results strongly recommend further evaluation of virotherapy and concomitant PD-1 immunotherapy in clinical studies.

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Metadata

Authors
Woller, N., Gürlevik, E., Fleischmann-Mundt, B., Schumacher, A., Knocke, S., Kloos, A. M., Saborowski, M., Geffers, R., Manns, M. P., Wirth, T. C., Kubicka, S., & Kühnel, F.
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2015-10
Volume
23
Issue
10
Pages
1630-1640
ISSN
1525-0016 (ISSN-L)
DOI
10.1038/mt.2015.115
OpenAlex
W1827720726
Cited by
186
References
10
FWCI
7.93
Type
journal article
Language
en
Open access
hybrid

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Woller, N., Gürlevik, E., Fleischmann-Mundt, B., Schumacher, A., Knocke, S., Kloos, A. M., Saborowski, M., Geffers, R., Manns, M. P., Wirth, T. C., Kubicka, S., & Kühnel, F. (2015). Viral Infection of Tumors Overcomes Resistance to PD-1-immunotherapy by Broadening Neoantigenome-directed T-cell Responses. Molecular Therapy. https://doi.org/10.1038/mt.2015.115

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.