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B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12
Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measur...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279427/ https://www.ncbi.nlm.nih.gov/pubmed/35831470 http://dx.doi.org/10.1038/s41598-022-16152-z |
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author | Hunter, Rae Imbach, Kathleen J. Zhou, Chengjing Dougan, Jodi Hamilton, Jamie A. G. Chen, Kevin Z. Do, Priscilla Townsel, Ashley Gibson, Greg Dreaden, Erik C. Waller, Edmund K. Haynes, Karmella A. Henry, Curtis J. Porter, Christopher C. |
author_facet | Hunter, Rae Imbach, Kathleen J. Zhou, Chengjing Dougan, Jodi Hamilton, Jamie A. G. Chen, Kevin Z. Do, Priscilla Townsel, Ashley Gibson, Greg Dreaden, Erik C. Waller, Edmund K. Haynes, Karmella A. Henry, Curtis J. Porter, Christopher C. |
author_sort | Hunter, Rae |
collection | PubMed |
description | Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measurable residual disease after induction chemotherapy showed differential cytokine expression, particularly IL-7, while single-cell RNA-sequencing revealed the expression of genes associated with immune exhaustion in immune cell subsets. We also found that the supernatant of leukemia cells suppressed T-cell function ex vivo. Modeling B-ALL in mice, we observed an altered tumor immune microenvironment, including compromised activation of T-cells and dendritic cells (DC). However, recombinant IL-12 (rIL-12) treatment of mice with B-ALL restored the levels of several pro-inflammatory cytokines and chemokines in the bone marrow and increased the number of splenic and bone marrow resident T-cells and DCs. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in genes associated with exhaustion, including Lag3, Tigit, and Il10, was abrogated with rIL-12 treatment. In addition, the cytolytic capacity of T-cells co-cultured with B-ALL cells was enhanced when IL-12 and blinatumomab treatments were combined. Overall, these results demonstrate that the leukemia immune suppressive microenvironment can be restored with rIL-12 treatment which has direct therapeutic implications. |
format | Online Article Text |
id | pubmed-9279427 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92794272022-07-15 B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12 Hunter, Rae Imbach, Kathleen J. Zhou, Chengjing Dougan, Jodi Hamilton, Jamie A. G. Chen, Kevin Z. Do, Priscilla Townsel, Ashley Gibson, Greg Dreaden, Erik C. Waller, Edmund K. Haynes, Karmella A. Henry, Curtis J. Porter, Christopher C. Sci Rep Article Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measurable residual disease after induction chemotherapy showed differential cytokine expression, particularly IL-7, while single-cell RNA-sequencing revealed the expression of genes associated with immune exhaustion in immune cell subsets. We also found that the supernatant of leukemia cells suppressed T-cell function ex vivo. Modeling B-ALL in mice, we observed an altered tumor immune microenvironment, including compromised activation of T-cells and dendritic cells (DC). However, recombinant IL-12 (rIL-12) treatment of mice with B-ALL restored the levels of several pro-inflammatory cytokines and chemokines in the bone marrow and increased the number of splenic and bone marrow resident T-cells and DCs. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in genes associated with exhaustion, including Lag3, Tigit, and Il10, was abrogated with rIL-12 treatment. In addition, the cytolytic capacity of T-cells co-cultured with B-ALL cells was enhanced when IL-12 and blinatumomab treatments were combined. Overall, these results demonstrate that the leukemia immune suppressive microenvironment can be restored with rIL-12 treatment which has direct therapeutic implications. Nature Publishing Group UK 2022-07-13 /pmc/articles/PMC9279427/ /pubmed/35831470 http://dx.doi.org/10.1038/s41598-022-16152-z Text en © The Author(s) 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Hunter, Rae Imbach, Kathleen J. Zhou, Chengjing Dougan, Jodi Hamilton, Jamie A. G. Chen, Kevin Z. Do, Priscilla Townsel, Ashley Gibson, Greg Dreaden, Erik C. Waller, Edmund K. Haynes, Karmella A. Henry, Curtis J. Porter, Christopher C. B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12 |
title | B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12 |
title_full | B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12 |
title_fullStr | B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12 |
title_full_unstemmed | B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12 |
title_short | B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12 |
title_sort | b-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by il-12 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279427/ https://www.ncbi.nlm.nih.gov/pubmed/35831470 http://dx.doi.org/10.1038/s41598-022-16152-z |
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