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Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer

Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transc...

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Autores principales: Palakurthi, Bhavana, Fross, Shaneann R., Guldner, Ian H., Aleksandrovic, Emilija, Liu, Xiyu, Martino, Anna K., Wang, Qingfei, Neff, Ryan A., Golomb, Samantha M., Lewis, Cheryl, Peng, Yan, Howe, Erin N., Zhang, Siyuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10101955/
https://www.ncbi.nlm.nih.gov/pubmed/37055410
http://dx.doi.org/10.1038/s41467-023-37727-y
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author Palakurthi, Bhavana
Fross, Shaneann R.
Guldner, Ian H.
Aleksandrovic, Emilija
Liu, Xiyu
Martino, Anna K.
Wang, Qingfei
Neff, Ryan A.
Golomb, Samantha M.
Lewis, Cheryl
Peng, Yan
Howe, Erin N.
Zhang, Siyuan
author_facet Palakurthi, Bhavana
Fross, Shaneann R.
Guldner, Ian H.
Aleksandrovic, Emilija
Liu, Xiyu
Martino, Anna K.
Wang, Qingfei
Neff, Ryan A.
Golomb, Samantha M.
Lewis, Cheryl
Peng, Yan
Howe, Erin N.
Zhang, Siyuan
author_sort Palakurthi, Bhavana
collection PubMed
description Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1’s role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.
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spelling pubmed-101019552023-04-15 Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer Palakurthi, Bhavana Fross, Shaneann R. Guldner, Ian H. Aleksandrovic, Emilija Liu, Xiyu Martino, Anna K. Wang, Qingfei Neff, Ryan A. Golomb, Samantha M. Lewis, Cheryl Peng, Yan Howe, Erin N. Zhang, Siyuan Nat Commun Article Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1’s role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients. Nature Publishing Group UK 2023-04-13 /pmc/articles/PMC10101955/ /pubmed/37055410 http://dx.doi.org/10.1038/s41467-023-37727-y Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 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
Palakurthi, Bhavana
Fross, Shaneann R.
Guldner, Ian H.
Aleksandrovic, Emilija
Liu, Xiyu
Martino, Anna K.
Wang, Qingfei
Neff, Ryan A.
Golomb, Samantha M.
Lewis, Cheryl
Peng, Yan
Howe, Erin N.
Zhang, Siyuan
Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer
title Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer
title_full Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer
title_fullStr Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer
title_full_unstemmed Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer
title_short Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer
title_sort targeting cxcl16 and stat1 augments immune checkpoint blockade therapy in triple-negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10101955/
https://www.ncbi.nlm.nih.gov/pubmed/37055410
http://dx.doi.org/10.1038/s41467-023-37727-y
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