Abstract
Purpose: Despite tumor resection being the first-line clinical care for glioblastoma (GBM) patients, nearly all preclinical immune therapy models intend to treat established GBM. Characterizing cytoreductive surgery-induced immune response combined with the administration of immune cytokines has the potential of offering a new treatment paradigm of immune therapy for GBMs. Experimental Design: We developed syngeneic orthotopic mouse GBM models of tumor resection and characterized the immune response of intact and resected tumors. We also created a highly secretable variant of immune cytokine IFNβ to enhance its release from engineered mouse mesenchymal stem cells (MSC-IFNβ) and assessed whether surgical resection of intracranial GBM tumor significantly enhanced the antitumor efficacy of targeted on-site delivery of encapsulated MSC-IFNβ. Results: We show that tumor debulking results in substantial reduction of myeloid-derived suppressor cells (MDSC) and simultaneous recruitment of CD4/CD8 T cells. This immune response significantly enhanced the antitumor efficacy of locally delivered encapsulated MSC-IFNβ via enhanced selective postsurgical infiltration of CD8 T cells and directly induced cell-cycle arrest in tumor cells, resulting in increased survival of mice. Utilizing encapsulated human MSC-IFNβ in resected orthotopic tumor xenografts of patient-derived GBM, we further show that IFNβ induces cell-cycle arrest followed by apoptosis, resulting in increased survival in immunocompromised mice despite their absence of an intact immune system. Conclusions: This study demonstrates the importance of syngeneic tumor resection models in developing cancer immunotherapies and emphasizes the translational potential of local delivery of immunotherapeutic agents in treating cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 7047-7058 |
| Number of pages | 12 |
| Journal | Clinical Cancer Research |
| Volume | 23 |
| Issue number | 22 |
| DOIs | |
| Publication status | Published - Nov 15 2017 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Tumor resection recruits effector T cells and boosts therapeutic efficacy of encapsulated stem cells expressing IFNβ in glioblastomas. / Choi, Sung Hugh; Stuckey, Daniel W.; Pignatta, Sara; Reinshagen, Clemens; Khalsa, Jasneet Kaur; Roozendaal, Nicolaas; Martinez-Quintanilla, Jordi; Tamura, Kaoru; Keles, Erhan; Shah, Khalid.
In: Clinical Cancer Research, Vol. 23, No. 22, 15.11.2017, p. 7047-7058.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tumor resection recruits effector T cells and boosts therapeutic efficacy of encapsulated stem cells expressing IFNβ in glioblastomas
AU - Choi, Sung Hugh
AU - Stuckey, Daniel W.
AU - Pignatta, Sara
AU - Reinshagen, Clemens
AU - Khalsa, Jasneet Kaur
AU - Roozendaal, Nicolaas
AU - Martinez-Quintanilla, Jordi
AU - Tamura, Kaoru
AU - Keles, Erhan
AU - Shah, Khalid
PY - 2017/11/15
Y1 - 2017/11/15
N2 - Purpose: Despite tumor resection being the first-line clinical care for glioblastoma (GBM) patients, nearly all preclinical immune therapy models intend to treat established GBM. Characterizing cytoreductive surgery-induced immune response combined with the administration of immune cytokines has the potential of offering a new treatment paradigm of immune therapy for GBMs. Experimental Design: We developed syngeneic orthotopic mouse GBM models of tumor resection and characterized the immune response of intact and resected tumors. We also created a highly secretable variant of immune cytokine IFNβ to enhance its release from engineered mouse mesenchymal stem cells (MSC-IFNβ) and assessed whether surgical resection of intracranial GBM tumor significantly enhanced the antitumor efficacy of targeted on-site delivery of encapsulated MSC-IFNβ. Results: We show that tumor debulking results in substantial reduction of myeloid-derived suppressor cells (MDSC) and simultaneous recruitment of CD4/CD8 T cells. This immune response significantly enhanced the antitumor efficacy of locally delivered encapsulated MSC-IFNβ via enhanced selective postsurgical infiltration of CD8 T cells and directly induced cell-cycle arrest in tumor cells, resulting in increased survival of mice. Utilizing encapsulated human MSC-IFNβ in resected orthotopic tumor xenografts of patient-derived GBM, we further show that IFNβ induces cell-cycle arrest followed by apoptosis, resulting in increased survival in immunocompromised mice despite their absence of an intact immune system. Conclusions: This study demonstrates the importance of syngeneic tumor resection models in developing cancer immunotherapies and emphasizes the translational potential of local delivery of immunotherapeutic agents in treating cancer.
AB - Purpose: Despite tumor resection being the first-line clinical care for glioblastoma (GBM) patients, nearly all preclinical immune therapy models intend to treat established GBM. Characterizing cytoreductive surgery-induced immune response combined with the administration of immune cytokines has the potential of offering a new treatment paradigm of immune therapy for GBMs. Experimental Design: We developed syngeneic orthotopic mouse GBM models of tumor resection and characterized the immune response of intact and resected tumors. We also created a highly secretable variant of immune cytokine IFNβ to enhance its release from engineered mouse mesenchymal stem cells (MSC-IFNβ) and assessed whether surgical resection of intracranial GBM tumor significantly enhanced the antitumor efficacy of targeted on-site delivery of encapsulated MSC-IFNβ. Results: We show that tumor debulking results in substantial reduction of myeloid-derived suppressor cells (MDSC) and simultaneous recruitment of CD4/CD8 T cells. This immune response significantly enhanced the antitumor efficacy of locally delivered encapsulated MSC-IFNβ via enhanced selective postsurgical infiltration of CD8 T cells and directly induced cell-cycle arrest in tumor cells, resulting in increased survival of mice. Utilizing encapsulated human MSC-IFNβ in resected orthotopic tumor xenografts of patient-derived GBM, we further show that IFNβ induces cell-cycle arrest followed by apoptosis, resulting in increased survival in immunocompromised mice despite their absence of an intact immune system. Conclusions: This study demonstrates the importance of syngeneic tumor resection models in developing cancer immunotherapies and emphasizes the translational potential of local delivery of immunotherapeutic agents in treating cancer.
UR - http://www.scopus.com/inward/record.url?scp=85034843583&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034843583&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-17-0077
DO - 10.1158/1078-0432.CCR-17-0077
M3 - Article
AN - SCOPUS:85034843583
VL - 23
SP - 7047
EP - 7058
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 22
ER -