Immune checkpoint blockade improves chemotherapy in the PyMT mammary carcinoma mouse model

Despite the success of immune checkpoint blockade in cancer, the number of patients that benefit from this revolutionary treatment option remains low. Therefore, efforts are being undertaken to sensitize tumors for immun
Despite the success of immune checkpoint blockade in cancer, the number of patients that benefit from this revolutionary treatment option remains low. Therefore, efforts are being undertaken to sensitize tumors for immune checkpoint blockade, which includes combining immune checkpoint blocking agents such as anti-PD-1 antibodies with standard of care treatments. Here we report that a combination of chemotherapy (doxorubicin) and immune checkpoint blockade (anti-PD-1 antibodies) induces superior tumor control compared to chemotherapy and immune checkpoint blockade alone in the murine autochthonous polyoma middle T oncogene-driven (PyMT) mammary tumor model. Using whole transcriptome analysis, we identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort. Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly natural killer cells (NK cells). Gene set enrichment analysis and bead-based ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 signaling improved NK cell cytotoxicity against PyMT cells in vitro. Taken together, our data support recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggest potential underlying mechanisms.
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Metadaten
Author:Evelyn Sirait-Fischer, Catherine Olesch, Annika F. Fink, Matthias Berkefeld, Arnaud Huard, Tobias Schmid, Kazuhiko Takeda, Bernhard Brüne, Andreas Weigert
URN:urn:nbn:de:hebis:30:3-562029
DOI:http://dx.doi.org/10.3389/fonc.2020.01771
ISSN:2234-943X
Parent Title (English):Frontiers in oncology
Publisher:Frontiers Media
Place of publication:Lausanne
Document Type:Article
Language:English
Date of Publication (online):2020/09/10
Date of first Publication:2020/09/10
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/10/08
Tag:cancer; chemotherapy; cytotoxic lymphocytes; immune checkpoint; immunotherapy
Volume:10
Issue:art. 1771
Pagenumber:14
First Page:1
Last Page:14
Note:
© 2020 Sirait-Fischer, Olesch, Fink, Berkefeld, Huard, Schmid, Takeda, Brüne and Weigert. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
HeBIS PPN:472528475
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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