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Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer

BACKGROUND: New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor s...

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Autores principales: Bazargan, Sarah, Bunch, Brittany, Ojwang‘, Awino Maureiq E., Blauvelt, Jamie, Landin, Annick, Ali, Johannes, Abrahams, Dominique, Cox, Cheryl, Hall, Amy M., Beatty, Matthew S., Poch, Michael, Rejniak, Katarzyna A., Pilon-Thomas, Shari
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602731/
https://www.ncbi.nlm.nih.gov/pubmed/37901214
http://dx.doi.org/10.3389/fimmu.2023.1275375
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author Bazargan, Sarah
Bunch, Brittany
Ojwang‘, Awino Maureiq E.
Blauvelt, Jamie
Landin, Annick
Ali, Johannes
Abrahams, Dominique
Cox, Cheryl
Hall, Amy M.
Beatty, Matthew S.
Poch, Michael
Rejniak, Katarzyna A.
Pilon-Thomas, Shari
author_facet Bazargan, Sarah
Bunch, Brittany
Ojwang‘, Awino Maureiq E.
Blauvelt, Jamie
Landin, Annick
Ali, Johannes
Abrahams, Dominique
Cox, Cheryl
Hall, Amy M.
Beatty, Matthew S.
Poch, Michael
Rejniak, Katarzyna A.
Pilon-Thomas, Shari
author_sort Bazargan, Sarah
collection PubMed
description BACKGROUND: New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor site. T cells infused into the bladder directly encounter immunosuppressive populations, such as myeloid derived suppressor cells (MDSCs), that can attenuate T cell responses. Intravesical instillation of gemcitabine can be used as a lymphodepleting agent to precondition the bladder microenvironment for infused T cell products. METHODS: Urine samples from bladder cancer patients and healthy donors were analyzed by flow cytometry and cytometric bead array for immune profiling and cytokine quantification. MDSCs were isolated from the urine and cocultured with stimulated T cells to assess effects on proliferation. An orthotopic murine model of bladder cancer was established using the MB49-OVA cell line and immune profiling was performed. MDSCs from tumor-bearing mice were cocultured with OT-I splenocytes to assess T cell proliferation. Mice received intravesical instillation of gemcitabine and depletion of immune cells was measured via flow cytometry. Bladder tumor growth of mice treated with intravesical gemcitabine, OT-I transgenic T cells, or combination was monitored via ultrasound measurement. RESULTS: In comparison to healthy donors, urine specimen from bladder cancer patients show high levels of MDSCs and cytokines associated with myeloid chemotaxis, T cell chemotaxis, and inflammation. T cells isolated from healthy donors were less proliferative when cocultured with MDSCs from the urine. Orthotopic murine bladder tumors also presented with high levels of MDSCs along with enrichment of cytokines found in the patient urine samples. MDSCs isolated from spleens of tumor-bearing mice exerted suppressive effects on the proliferation of OT-I T cells. Intravesical instillation of gemcitabine reduced overall immune cells, MDSCs, and T cells in orthotopic bladder tumors. Combination treatment with gemcitabine and OT-I T cells resulted in sustained anti-tumor responses in comparison to monotherapy treatments. CONCLUSION: MDSCs are enriched within the microenvironment of bladder tumors and are suppressive to T cells. Gemcitabine can be used to lymphodeplete bladder tumors and precondition the microenvironment for intravesical ACT.
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spelling pubmed-106027312023-10-27 Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer Bazargan, Sarah Bunch, Brittany Ojwang‘, Awino Maureiq E. Blauvelt, Jamie Landin, Annick Ali, Johannes Abrahams, Dominique Cox, Cheryl Hall, Amy M. Beatty, Matthew S. Poch, Michael Rejniak, Katarzyna A. Pilon-Thomas, Shari Front Immunol Immunology BACKGROUND: New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor site. T cells infused into the bladder directly encounter immunosuppressive populations, such as myeloid derived suppressor cells (MDSCs), that can attenuate T cell responses. Intravesical instillation of gemcitabine can be used as a lymphodepleting agent to precondition the bladder microenvironment for infused T cell products. METHODS: Urine samples from bladder cancer patients and healthy donors were analyzed by flow cytometry and cytometric bead array for immune profiling and cytokine quantification. MDSCs were isolated from the urine and cocultured with stimulated T cells to assess effects on proliferation. An orthotopic murine model of bladder cancer was established using the MB49-OVA cell line and immune profiling was performed. MDSCs from tumor-bearing mice were cocultured with OT-I splenocytes to assess T cell proliferation. Mice received intravesical instillation of gemcitabine and depletion of immune cells was measured via flow cytometry. Bladder tumor growth of mice treated with intravesical gemcitabine, OT-I transgenic T cells, or combination was monitored via ultrasound measurement. RESULTS: In comparison to healthy donors, urine specimen from bladder cancer patients show high levels of MDSCs and cytokines associated with myeloid chemotaxis, T cell chemotaxis, and inflammation. T cells isolated from healthy donors were less proliferative when cocultured with MDSCs from the urine. Orthotopic murine bladder tumors also presented with high levels of MDSCs along with enrichment of cytokines found in the patient urine samples. MDSCs isolated from spleens of tumor-bearing mice exerted suppressive effects on the proliferation of OT-I T cells. Intravesical instillation of gemcitabine reduced overall immune cells, MDSCs, and T cells in orthotopic bladder tumors. Combination treatment with gemcitabine and OT-I T cells resulted in sustained anti-tumor responses in comparison to monotherapy treatments. CONCLUSION: MDSCs are enriched within the microenvironment of bladder tumors and are suppressive to T cells. Gemcitabine can be used to lymphodeplete bladder tumors and precondition the microenvironment for intravesical ACT. Frontiers Media S.A. 2023-10-12 /pmc/articles/PMC10602731/ /pubmed/37901214 http://dx.doi.org/10.3389/fimmu.2023.1275375 Text en Copyright © 2023 Bazargan, Bunch, Ojwang‘, Blauvelt, Landin, Ali, Abrahams, Cox, Hall, Beatty, Poch, Rejniak and Pilon-Thomas 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
Bazargan, Sarah
Bunch, Brittany
Ojwang‘, Awino Maureiq E.
Blauvelt, Jamie
Landin, Annick
Ali, Johannes
Abrahams, Dominique
Cox, Cheryl
Hall, Amy M.
Beatty, Matthew S.
Poch, Michael
Rejniak, Katarzyna A.
Pilon-Thomas, Shari
Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer
title Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer
title_full Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer
title_fullStr Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer
title_full_unstemmed Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer
title_short Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer
title_sort targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602731/
https://www.ncbi.nlm.nih.gov/pubmed/37901214
http://dx.doi.org/10.3389/fimmu.2023.1275375
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