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Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer

Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects a...

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Autores principales: Lee, Joyce V., Housley, Filomena, Yau, Christina, Nakagawa, Rachel, Winkler, Juliane, Anttila, Johanna M., Munne, Pauliina M., Savelius, Mariel, Houlahan, Kathleen E., Van de Mark, Daniel, Hemmati, Golzar, Hernandez, Grace A., Zhang, Yibing, Samson, Susan, Baas, Carole, Kok, Marleen, Esserman, Laura J., van ‘t Veer, Laura J., Rugo, Hope S., Curtis, Christina, Klefström, Juha, Matloubian, Mehrdad, Goga, Andrei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237085/
https://www.ncbi.nlm.nih.gov/pubmed/35760778
http://dx.doi.org/10.1038/s41467-022-31238-y
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author Lee, Joyce V.
Housley, Filomena
Yau, Christina
Nakagawa, Rachel
Winkler, Juliane
Anttila, Johanna M.
Munne, Pauliina M.
Savelius, Mariel
Houlahan, Kathleen E.
Van de Mark, Daniel
Hemmati, Golzar
Hernandez, Grace A.
Zhang, Yibing
Samson, Susan
Baas, Carole
Kok, Marleen
Esserman, Laura J.
van ‘t Veer, Laura J.
Rugo, Hope S.
Curtis, Christina
Klefström, Juha
Matloubian, Mehrdad
Goga, Andrei
author_facet Lee, Joyce V.
Housley, Filomena
Yau, Christina
Nakagawa, Rachel
Winkler, Juliane
Anttila, Johanna M.
Munne, Pauliina M.
Savelius, Mariel
Houlahan, Kathleen E.
Van de Mark, Daniel
Hemmati, Golzar
Hernandez, Grace A.
Zhang, Yibing
Samson, Susan
Baas, Carole
Kok, Marleen
Esserman, Laura J.
van ‘t Veer, Laura J.
Rugo, Hope S.
Curtis, Christina
Klefström, Juha
Matloubian, Mehrdad
Goga, Andrei
author_sort Lee, Joyce V.
collection PubMed
description Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.
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spelling pubmed-92370852022-06-29 Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer Lee, Joyce V. Housley, Filomena Yau, Christina Nakagawa, Rachel Winkler, Juliane Anttila, Johanna M. Munne, Pauliina M. Savelius, Mariel Houlahan, Kathleen E. Van de Mark, Daniel Hemmati, Golzar Hernandez, Grace A. Zhang, Yibing Samson, Susan Baas, Carole Kok, Marleen Esserman, Laura J. van ‘t Veer, Laura J. Rugo, Hope S. Curtis, Christina Klefström, Juha Matloubian, Mehrdad Goga, Andrei Nat Commun Article Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors. Nature Publishing Group UK 2022-06-27 /pmc/articles/PMC9237085/ /pubmed/35760778 http://dx.doi.org/10.1038/s41467-022-31238-y Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lee, Joyce V.
Housley, Filomena
Yau, Christina
Nakagawa, Rachel
Winkler, Juliane
Anttila, Johanna M.
Munne, Pauliina M.
Savelius, Mariel
Houlahan, Kathleen E.
Van de Mark, Daniel
Hemmati, Golzar
Hernandez, Grace A.
Zhang, Yibing
Samson, Susan
Baas, Carole
Kok, Marleen
Esserman, Laura J.
van ‘t Veer, Laura J.
Rugo, Hope S.
Curtis, Christina
Klefström, Juha
Matloubian, Mehrdad
Goga, Andrei
Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
title Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
title_full Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
title_fullStr Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
title_full_unstemmed Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
title_short Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
title_sort combinatorial immunotherapies overcome myc-driven immune evasion in triple negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237085/
https://www.ncbi.nlm.nih.gov/pubmed/35760778
http://dx.doi.org/10.1038/s41467-022-31238-y
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