Cargando…

Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth

BACKGROUND: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the con...

Descripción completa

Detalles Bibliográficos
Autores principales: van der Most, Robbert G., Currie, Andrew J., Cleaver, Amanda L., Salmons, Joanne, Nowak, Anna K., Mahendran, Sathish, Larma, Irma, Prosser, Amy, Robinson, Bruce W. S., Smyth, Mark J., Scalzo, Anthony A., Degli-Esposti, Mariapia A., Lake, Richard A.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734989/
https://www.ncbi.nlm.nih.gov/pubmed/19746156
http://dx.doi.org/10.1371/journal.pone.0006982
_version_ 1782171239904706560
author van der Most, Robbert G.
Currie, Andrew J.
Cleaver, Amanda L.
Salmons, Joanne
Nowak, Anna K.
Mahendran, Sathish
Larma, Irma
Prosser, Amy
Robinson, Bruce W. S.
Smyth, Mark J.
Scalzo, Anthony A.
Degli-Esposti, Mariapia A.
Lake, Richard A.
author_facet van der Most, Robbert G.
Currie, Andrew J.
Cleaver, Amanda L.
Salmons, Joanne
Nowak, Anna K.
Mahendran, Sathish
Larma, Irma
Prosser, Amy
Robinson, Bruce W. S.
Smyth, Mark J.
Scalzo, Anthony A.
Degli-Esposti, Mariapia A.
Lake, Richard A.
author_sort van der Most, Robbert G.
collection PubMed
description BACKGROUND: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. METHODS AND FINDINGS: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies. CONCLUSION: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion.
format Text
id pubmed-2734989
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-27349892009-09-10 Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth van der Most, Robbert G. Currie, Andrew J. Cleaver, Amanda L. Salmons, Joanne Nowak, Anna K. Mahendran, Sathish Larma, Irma Prosser, Amy Robinson, Bruce W. S. Smyth, Mark J. Scalzo, Anthony A. Degli-Esposti, Mariapia A. Lake, Richard A. PLoS One Research Article BACKGROUND: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. METHODS AND FINDINGS: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies. CONCLUSION: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion. Public Library of Science 2009-09-10 /pmc/articles/PMC2734989/ /pubmed/19746156 http://dx.doi.org/10.1371/journal.pone.0006982 Text en van der Most et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
van der Most, Robbert G.
Currie, Andrew J.
Cleaver, Amanda L.
Salmons, Joanne
Nowak, Anna K.
Mahendran, Sathish
Larma, Irma
Prosser, Amy
Robinson, Bruce W. S.
Smyth, Mark J.
Scalzo, Anthony A.
Degli-Esposti, Mariapia A.
Lake, Richard A.
Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth
title Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth
title_full Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth
title_fullStr Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth
title_full_unstemmed Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth
title_short Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth
title_sort cyclophosphamide chemotherapy sensitizes tumor cells to trail-dependent cd8 t cell-mediated immune attack resulting in suppression of tumor growth
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734989/
https://www.ncbi.nlm.nih.gov/pubmed/19746156
http://dx.doi.org/10.1371/journal.pone.0006982
work_keys_str_mv AT vandermostrobbertg cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT currieandrewj cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT cleaveramandal cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT salmonsjoanne cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT nowakannak cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT mahendransathish cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT larmairma cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT prosseramy cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT robinsonbrucews cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT smythmarkj cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT scalzoanthonya cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT degliespostimariapiaa cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth
AT lakericharda cyclophosphamidechemotherapysensitizestumorcellstotraildependentcd8tcellmediatedimmuneattackresultinginsuppressionoftumorgrowth