A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo
Aggressive forms of breast cancer, such as Her2+ and triple negative breast cancer (TNBC), are enriched in breast cancer stem cells (BCSC) and have limited therapeutic options. BCSC represent a key cellular reservoir for relapse, metastatic progression and therapeutic resistance. Their ability to re...
Main Authors: | , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Taylor & Francis Group
2018-03-01
|
Series: | OncoImmunology |
Subjects: | |
Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1408746 |
id |
doaj-c079ae8e96ed438eb8a585b30145b3d0 |
---|---|
record_format |
Article |
spelling |
doaj-c079ae8e96ed438eb8a585b30145b3d02020-11-25T03:28:12ZengTaylor & Francis GroupOncoImmunology2162-402X2018-03-017310.1080/2162402X.2017.14087461408746A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivoElisabetta Bolli0John P. O'Rourke1Laura Conti2Stefania Lanzardo3Valeria Rolih4Jayne M. Christen5Giuseppina Barutello6Marco Forni7Federica Pericle8Federica Cavallo9University of TorinoAgilvax, IncUniversity of TorinoUniversity of TorinoUniversity of TorinoAgilvax, IncUniversity of TorinoUniversity of TorinoAgilvax, IncUniversity of TorinoAggressive forms of breast cancer, such as Her2+ and triple negative breast cancer (TNBC), are enriched in breast cancer stem cells (BCSC) and have limited therapeutic options. BCSC represent a key cellular reservoir for relapse, metastatic progression and therapeutic resistance. Their ability to resist common cytotoxic therapies relies on different mechanisms, including improved detoxification. The cystine-glutamate antiporter protein xCT (SLC7A11) regulates cystine intake, conversion to cysteine and subsequent glutathione synthesis, protecting cells against oxidative and chemical insults. Our previous work showed that xCT is highly expressed in tumorspheres derived from breast cancer cell lines and downregulation of xCT altered BCSC function in vitro and inhibited pulmonary metastases in vivo. We further strengthened these observations by developing a virus-like-particle (VLP; AX09-0M6) immunotherapy targeting the xCT protein. AX09-0M6 elicited a strong antibody response against xCT including high levels of IgG2a antibody. IgG isolated from AX09-0M6 treated mice bound to tumorspheres, inhibited xCT function as assessed by reactive oxygen species generation and decreased BCSC growth and self-renewal. To assess if AX09-0M6 impacts BCSC in vivo seeding, Her2+ TUBO-derived tumorspheres were injected into the tail vein of AX09-0M6 or control treated female BALB/c mice. AX09-0M6 significantly inhibited formation of pulmonary nodules. To evaluate its ability to impact metastases, AX09-0M6 was administered to mice with established subcutaneous 4T1 tumors. AX09-0M6 administration significantly hampered tumor growth and development of pulmonary metastases. These data show that a VLP-based immunization approach inhibits xCT activity, impacts BCSC biology and significantly reduces metastatic progression in preclinical models.http://dx.doi.org/10.1080/2162402X.2017.1408746breast cancercancer stem cellimmunotherapyvirus like-particlexct |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Elisabetta Bolli John P. O'Rourke Laura Conti Stefania Lanzardo Valeria Rolih Jayne M. Christen Giuseppina Barutello Marco Forni Federica Pericle Federica Cavallo |
spellingShingle |
Elisabetta Bolli John P. O'Rourke Laura Conti Stefania Lanzardo Valeria Rolih Jayne M. Christen Giuseppina Barutello Marco Forni Federica Pericle Federica Cavallo A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo OncoImmunology breast cancer cancer stem cell immunotherapy virus like-particle xct |
author_facet |
Elisabetta Bolli John P. O'Rourke Laura Conti Stefania Lanzardo Valeria Rolih Jayne M. Christen Giuseppina Barutello Marco Forni Federica Pericle Federica Cavallo |
author_sort |
Elisabetta Bolli |
title |
A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo |
title_short |
A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo |
title_full |
A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo |
title_fullStr |
A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo |
title_full_unstemmed |
A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo |
title_sort |
virus-like-particle immunotherapy targeting epitope-specific anti-xct expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2018-03-01 |
description |
Aggressive forms of breast cancer, such as Her2+ and triple negative breast cancer (TNBC), are enriched in breast cancer stem cells (BCSC) and have limited therapeutic options. BCSC represent a key cellular reservoir for relapse, metastatic progression and therapeutic resistance. Their ability to resist common cytotoxic therapies relies on different mechanisms, including improved detoxification. The cystine-glutamate antiporter protein xCT (SLC7A11) regulates cystine intake, conversion to cysteine and subsequent glutathione synthesis, protecting cells against oxidative and chemical insults. Our previous work showed that xCT is highly expressed in tumorspheres derived from breast cancer cell lines and downregulation of xCT altered BCSC function in vitro and inhibited pulmonary metastases in vivo. We further strengthened these observations by developing a virus-like-particle (VLP; AX09-0M6) immunotherapy targeting the xCT protein. AX09-0M6 elicited a strong antibody response against xCT including high levels of IgG2a antibody. IgG isolated from AX09-0M6 treated mice bound to tumorspheres, inhibited xCT function as assessed by reactive oxygen species generation and decreased BCSC growth and self-renewal. To assess if AX09-0M6 impacts BCSC in vivo seeding, Her2+ TUBO-derived tumorspheres were injected into the tail vein of AX09-0M6 or control treated female BALB/c mice. AX09-0M6 significantly inhibited formation of pulmonary nodules. To evaluate its ability to impact metastases, AX09-0M6 was administered to mice with established subcutaneous 4T1 tumors. AX09-0M6 administration significantly hampered tumor growth and development of pulmonary metastases. These data show that a VLP-based immunization approach inhibits xCT activity, impacts BCSC biology and significantly reduces metastatic progression in preclinical models. |
topic |
breast cancer cancer stem cell immunotherapy virus like-particle xct |
url |
http://dx.doi.org/10.1080/2162402X.2017.1408746 |
work_keys_str_mv |
AT elisabettabolli aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT johnporourke aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT lauraconti aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT stefanialanzardo aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT valeriarolih aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT jaynemchristen aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT giuseppinabarutello aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT marcoforni aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT federicapericle aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT federicacavallo aviruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT elisabettabolli viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT johnporourke viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT lauraconti viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT stefanialanzardo viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT valeriarolih viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT jaynemchristen viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT giuseppinabarutello viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT marcoforni viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT federicapericle viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo AT federicacavallo viruslikeparticleimmunotherapytargetingepitopespecificantixctexpressedoncancerstemcellinhibitstheprogressionofmetastaticcancerinvivo |
_version_ |
1724585715043401728 |