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MK2 drives progression of pancreas and colon cancers by suppressing CD8(+) T cell cytotoxic function and is a potential immunotherapy target
BACKGROUND: Immune cell composition is a critical and dynamic component of the tumor microenvironment, which has an impact on immunosuppression and progression of cancer. T cells, especially CD8(+) T cells, are one of the major immune cell types responsible for tumor cell killing employing receptor-...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10321668/ https://www.ncbi.nlm.nih.gov/pubmed/37415974 http://dx.doi.org/10.3389/fimmu.2023.1212100 |
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author | Jacenik, Damian Lebish, Eric J. Beswick, Ellen J. |
author_facet | Jacenik, Damian Lebish, Eric J. Beswick, Ellen J. |
author_sort | Jacenik, Damian |
collection | PubMed |
description | BACKGROUND: Immune cell composition is a critical and dynamic component of the tumor microenvironment, which has an impact on immunosuppression and progression of cancer. T cells, especially CD8(+) T cells, are one of the major immune cell types responsible for tumor cell killing employing receptor-ligand mediated apoptosis and/or releasing lytic granules among others. Accumulating evidence highlighted that adoptive transfer of activated and/or modified immune cells can enhance anti-tumorigenic immune responses and serve as promising therapy approach for patients with cancers. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a serine/threonine protein kinase, which controls production and secretion of numerous pro-inflammatory cytokines and chemokines involved in tumorigenesis. However, limited efforts have been made to learn how MK2 may affects CD8(+) T cell action and function in the tumor microenvironment especially in gastrointestinal cancers. METHODS: To explore the therapeutic potential of MK2 in the immune response mediated by CD8(+) T cells, RAG1 knockout mice with PK5L1940 and BRAF cells-derived allograft tumors were treated with WT or MK2 knockout CD8(+) T cells. The phenotype of CD8(+) T cells with MK2 depletion were evaluated in vitro. Immunofluorescence staining, real-time PCR and multiplex analysis were utilized to estimate the expression of apoptotic and lytic factors. RESULTS: Here, we show that CD8(+) T cells with MK2 depletion prevent gastrointestinal cancer growth, which is accompanied by enhanced expression and secretion of factors related to apoptosis. Moreover, using in vitro and in vivo approaches, we found that depletion of MK2 lead to hyperactivation of CD8(+) T cells and enhanced anti-tumor immunity. CONCLUSION: Overall, we documented that MK2 drives the progression of gastrointestinal cancers and prevents immune response generated by CD8(+) T cells suggesting potential implications of MK2 in the immunotherapy of gastrointestinal cancers. |
format | Online Article Text |
id | pubmed-10321668 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-103216682023-07-06 MK2 drives progression of pancreas and colon cancers by suppressing CD8(+) T cell cytotoxic function and is a potential immunotherapy target Jacenik, Damian Lebish, Eric J. Beswick, Ellen J. Front Immunol Immunology BACKGROUND: Immune cell composition is a critical and dynamic component of the tumor microenvironment, which has an impact on immunosuppression and progression of cancer. T cells, especially CD8(+) T cells, are one of the major immune cell types responsible for tumor cell killing employing receptor-ligand mediated apoptosis and/or releasing lytic granules among others. Accumulating evidence highlighted that adoptive transfer of activated and/or modified immune cells can enhance anti-tumorigenic immune responses and serve as promising therapy approach for patients with cancers. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a serine/threonine protein kinase, which controls production and secretion of numerous pro-inflammatory cytokines and chemokines involved in tumorigenesis. However, limited efforts have been made to learn how MK2 may affects CD8(+) T cell action and function in the tumor microenvironment especially in gastrointestinal cancers. METHODS: To explore the therapeutic potential of MK2 in the immune response mediated by CD8(+) T cells, RAG1 knockout mice with PK5L1940 and BRAF cells-derived allograft tumors were treated with WT or MK2 knockout CD8(+) T cells. The phenotype of CD8(+) T cells with MK2 depletion were evaluated in vitro. Immunofluorescence staining, real-time PCR and multiplex analysis were utilized to estimate the expression of apoptotic and lytic factors. RESULTS: Here, we show that CD8(+) T cells with MK2 depletion prevent gastrointestinal cancer growth, which is accompanied by enhanced expression and secretion of factors related to apoptosis. Moreover, using in vitro and in vivo approaches, we found that depletion of MK2 lead to hyperactivation of CD8(+) T cells and enhanced anti-tumor immunity. CONCLUSION: Overall, we documented that MK2 drives the progression of gastrointestinal cancers and prevents immune response generated by CD8(+) T cells suggesting potential implications of MK2 in the immunotherapy of gastrointestinal cancers. Frontiers Media S.A. 2023-06-21 /pmc/articles/PMC10321668/ /pubmed/37415974 http://dx.doi.org/10.3389/fimmu.2023.1212100 Text en Copyright © 2023 Jacenik, Lebish and Beswick https://creativecommons.org/licenses/by/4.0/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. |
spellingShingle | Immunology Jacenik, Damian Lebish, Eric J. Beswick, Ellen J. MK2 drives progression of pancreas and colon cancers by suppressing CD8(+) T cell cytotoxic function and is a potential immunotherapy target |
title | MK2 drives progression of pancreas and colon cancers by suppressing CD8(+) T cell cytotoxic function and is a potential immunotherapy target |
title_full | MK2 drives progression of pancreas and colon cancers by suppressing CD8(+) T cell cytotoxic function and is a potential immunotherapy target |
title_fullStr | MK2 drives progression of pancreas and colon cancers by suppressing CD8(+) T cell cytotoxic function and is a potential immunotherapy target |
title_full_unstemmed | MK2 drives progression of pancreas and colon cancers by suppressing CD8(+) T cell cytotoxic function and is a potential immunotherapy target |
title_short | MK2 drives progression of pancreas and colon cancers by suppressing CD8(+) T cell cytotoxic function and is a potential immunotherapy target |
title_sort | mk2 drives progression of pancreas and colon cancers by suppressing cd8(+) t cell cytotoxic function and is a potential immunotherapy target |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10321668/ https://www.ncbi.nlm.nih.gov/pubmed/37415974 http://dx.doi.org/10.3389/fimmu.2023.1212100 |
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