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T(h)17, T(h)22, and Myeloid-Derived Suppressor Cell Population Dynamics and Response to IL-6 in 4T1 Mammary Carcinoma
Immunotherapies relying on type 1 immunity have shown robust clinical responses in some cancers yet remain relatively ineffective in solid breast tumors. Polarization toward type 2 immunity and expansion of myeloid-derived suppressor cells (MDSC) confer resistance to therapy, though it remains uncle...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498998/ https://www.ncbi.nlm.nih.gov/pubmed/36142210 http://dx.doi.org/10.3390/ijms231810299 |
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author | Rasé, Viva J. Hayward, Reid Haughian, James M. Pullen, Nicholas A. |
author_facet | Rasé, Viva J. Hayward, Reid Haughian, James M. Pullen, Nicholas A. |
author_sort | Rasé, Viva J. |
collection | PubMed |
description | Immunotherapies relying on type 1 immunity have shown robust clinical responses in some cancers yet remain relatively ineffective in solid breast tumors. Polarization toward type 2 immunity and expansion of myeloid-derived suppressor cells (MDSC) confer resistance to therapy, though it remains unclear whether polarization toward type 3 immunity occurs or has a similar effect. Therefore, we investigated the involvement of type 3 T(h)17 and T(h)22 cells and their association with expanding MDSC populations in the 4T1 mouse mammary carcinoma model. T(h)17 and T(h)22 were detected in the earliest measurable mass at d 14 and remained present until the final sampling on d 28. In peripheral organs, T(h)17 populations were significantly higher than the non-tumor bearing control and peaked early at d 7, before a palpable tumor had formed. Peripheral T(h)22 proportions were also significantly increased, though at later times when tumors were established. To further address the mechanism underlying type 3 immune cell and MDSC recruitment, we used CRISPR-Cas9 to knock out 4T1 tumor production of interleukin-6 (4T1-IL-6-KO), which functions in myelopoiesis, MDSC recruitment, and T(h) maturation. While 4T1-IL-6-KO tumor growth was similar to the control, the reduced IL-6 significantly expanded the total CD4(+) T(h) population and T(h)17 in tumors, while T(h)22 and MDSC were reduced in all tissues; this suggests that clinical IL-6 depletion combined with immunotherapy could improve outcomes. In sum, 4T1 mammary carcinomas secrete IL-6 and other factors, to polarize and reshape T(h) populations and expand distinct T(h)17 and T(h)22 populations, which may facilitate tumor growth and confer immunotherapy resistance. |
format | Online Article Text |
id | pubmed-9498998 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94989982022-09-23 T(h)17, T(h)22, and Myeloid-Derived Suppressor Cell Population Dynamics and Response to IL-6 in 4T1 Mammary Carcinoma Rasé, Viva J. Hayward, Reid Haughian, James M. Pullen, Nicholas A. Int J Mol Sci Article Immunotherapies relying on type 1 immunity have shown robust clinical responses in some cancers yet remain relatively ineffective in solid breast tumors. Polarization toward type 2 immunity and expansion of myeloid-derived suppressor cells (MDSC) confer resistance to therapy, though it remains unclear whether polarization toward type 3 immunity occurs or has a similar effect. Therefore, we investigated the involvement of type 3 T(h)17 and T(h)22 cells and their association with expanding MDSC populations in the 4T1 mouse mammary carcinoma model. T(h)17 and T(h)22 were detected in the earliest measurable mass at d 14 and remained present until the final sampling on d 28. In peripheral organs, T(h)17 populations were significantly higher than the non-tumor bearing control and peaked early at d 7, before a palpable tumor had formed. Peripheral T(h)22 proportions were also significantly increased, though at later times when tumors were established. To further address the mechanism underlying type 3 immune cell and MDSC recruitment, we used CRISPR-Cas9 to knock out 4T1 tumor production of interleukin-6 (4T1-IL-6-KO), which functions in myelopoiesis, MDSC recruitment, and T(h) maturation. While 4T1-IL-6-KO tumor growth was similar to the control, the reduced IL-6 significantly expanded the total CD4(+) T(h) population and T(h)17 in tumors, while T(h)22 and MDSC were reduced in all tissues; this suggests that clinical IL-6 depletion combined with immunotherapy could improve outcomes. In sum, 4T1 mammary carcinomas secrete IL-6 and other factors, to polarize and reshape T(h) populations and expand distinct T(h)17 and T(h)22 populations, which may facilitate tumor growth and confer immunotherapy resistance. MDPI 2022-09-07 /pmc/articles/PMC9498998/ /pubmed/36142210 http://dx.doi.org/10.3390/ijms231810299 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Rasé, Viva J. Hayward, Reid Haughian, James M. Pullen, Nicholas A. T(h)17, T(h)22, and Myeloid-Derived Suppressor Cell Population Dynamics and Response to IL-6 in 4T1 Mammary Carcinoma |
title | T(h)17, T(h)22, and Myeloid-Derived Suppressor Cell Population Dynamics and Response to IL-6 in 4T1 Mammary Carcinoma |
title_full | T(h)17, T(h)22, and Myeloid-Derived Suppressor Cell Population Dynamics and Response to IL-6 in 4T1 Mammary Carcinoma |
title_fullStr | T(h)17, T(h)22, and Myeloid-Derived Suppressor Cell Population Dynamics and Response to IL-6 in 4T1 Mammary Carcinoma |
title_full_unstemmed | T(h)17, T(h)22, and Myeloid-Derived Suppressor Cell Population Dynamics and Response to IL-6 in 4T1 Mammary Carcinoma |
title_short | T(h)17, T(h)22, and Myeloid-Derived Suppressor Cell Population Dynamics and Response to IL-6 in 4T1 Mammary Carcinoma |
title_sort | t(h)17, t(h)22, and myeloid-derived suppressor cell population dynamics and response to il-6 in 4t1 mammary carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498998/ https://www.ncbi.nlm.nih.gov/pubmed/36142210 http://dx.doi.org/10.3390/ijms231810299 |
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