Cargando…

Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer

OX40 is a costimulatory receptor that potentiates proliferation, survival, memory formation, and effector function of CD4(+) and CD8(+) T-cells, while overcoming the suppressive activity of regulatory T-cells (Tregs). Here, we explored the combination of an OX40L fusion protein (OX40L-FP) with a pox...

Descripción completa

Detalles Bibliográficos
Autores principales: Malamas, Anthony S., Hammond, Scott A., Schlom, Jeffrey, Hodge, James W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710887/
https://www.ncbi.nlm.nih.gov/pubmed/29207606
http://dx.doi.org/10.18632/oncotarget.19967
_version_ 1783282960901865472
author Malamas, Anthony S.
Hammond, Scott A.
Schlom, Jeffrey
Hodge, James W.
author_facet Malamas, Anthony S.
Hammond, Scott A.
Schlom, Jeffrey
Hodge, James W.
author_sort Malamas, Anthony S.
collection PubMed
description OX40 is a costimulatory receptor that potentiates proliferation, survival, memory formation, and effector function of CD4(+) and CD8(+) T-cells, while overcoming the suppressive activity of regulatory T-cells (Tregs). Here, we explored the combination of an OX40L fusion protein (OX40L-FP) with a poxvirus-based cancer vaccine (MVA-Twist-TRICOM) to inhibit tumor metastasis in the 4T1 murine breast cancer model. Contrary to the single agent treatments, the combination therapy significantly decreased the number of metastatic colonies per lung and prolonged survival. Depletion studies demonstrated that these effects were mediated by both CD4(+) and CD8(+) T-cells. The combination therapy a) increased the total number of T-cells in the CD4(+)Foxp3(-) population and the CD4(+) central and effector memory subsets within the lung, spleen, and draining lymph node, b) enhanced infiltration of CD4(+) T-cells into metastatic areas of the lung, and (c) increased the number of functional CD8(+) T-cells that produced IFNγ and TNFα. The combination therapy also promoted the development of KLRG1(-)CD127(+) memory precursor CD8(+) T-cells, while reducing those with a KLRG1(+) terminally differentiated phenotype. Moreover, the combination of OX40L-FP and vaccine induced greater CD4(+) and CD8(+) Twist-specific responses. In addition, Tregs isolated from mice receiving the combination were also less immunosuppressive in ex-vivo proliferation assays than those from the OX40L-FP and MVA-Twist-TRICOM monotherapy groups. Such results provide the rationale to combine co-stimulatory agonists with cancer vaccines for the treatment of tumor metastasis.
format Online
Article
Text
id pubmed-5710887
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-57108872017-12-04 Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer Malamas, Anthony S. Hammond, Scott A. Schlom, Jeffrey Hodge, James W. Oncotarget Research Paper OX40 is a costimulatory receptor that potentiates proliferation, survival, memory formation, and effector function of CD4(+) and CD8(+) T-cells, while overcoming the suppressive activity of regulatory T-cells (Tregs). Here, we explored the combination of an OX40L fusion protein (OX40L-FP) with a poxvirus-based cancer vaccine (MVA-Twist-TRICOM) to inhibit tumor metastasis in the 4T1 murine breast cancer model. Contrary to the single agent treatments, the combination therapy significantly decreased the number of metastatic colonies per lung and prolonged survival. Depletion studies demonstrated that these effects were mediated by both CD4(+) and CD8(+) T-cells. The combination therapy a) increased the total number of T-cells in the CD4(+)Foxp3(-) population and the CD4(+) central and effector memory subsets within the lung, spleen, and draining lymph node, b) enhanced infiltration of CD4(+) T-cells into metastatic areas of the lung, and (c) increased the number of functional CD8(+) T-cells that produced IFNγ and TNFα. The combination therapy also promoted the development of KLRG1(-)CD127(+) memory precursor CD8(+) T-cells, while reducing those with a KLRG1(+) terminally differentiated phenotype. Moreover, the combination of OX40L-FP and vaccine induced greater CD4(+) and CD8(+) Twist-specific responses. In addition, Tregs isolated from mice receiving the combination were also less immunosuppressive in ex-vivo proliferation assays than those from the OX40L-FP and MVA-Twist-TRICOM monotherapy groups. Such results provide the rationale to combine co-stimulatory agonists with cancer vaccines for the treatment of tumor metastasis. Impact Journals LLC 2017-08-05 /pmc/articles/PMC5710887/ /pubmed/29207606 http://dx.doi.org/10.18632/oncotarget.19967 Text en Copyright: © 2017 Malamas et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Malamas, Anthony S.
Hammond, Scott A.
Schlom, Jeffrey
Hodge, James W.
Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer
title Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer
title_full Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer
title_fullStr Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer
title_full_unstemmed Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer
title_short Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer
title_sort combination therapy with an ox40l fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710887/
https://www.ncbi.nlm.nih.gov/pubmed/29207606
http://dx.doi.org/10.18632/oncotarget.19967
work_keys_str_mv AT malamasanthonys combinationtherapywithanox40lfusionproteinandavaccinetargetingthetranscriptionfactortwistinhibitsmetastasisinamurinemodelofbreastcancer
AT hammondscotta combinationtherapywithanox40lfusionproteinandavaccinetargetingthetranscriptionfactortwistinhibitsmetastasisinamurinemodelofbreastcancer
AT schlomjeffrey combinationtherapywithanox40lfusionproteinandavaccinetargetingthetranscriptionfactortwistinhibitsmetastasisinamurinemodelofbreastcancer
AT hodgejamesw combinationtherapywithanox40lfusionproteinandavaccinetargetingthetranscriptionfactortwistinhibitsmetastasisinamurinemodelofbreastcancer