Tumor resection recruits effector T cells and boosts therapeutic efficacy of encapsulated stem cells expressing IFNβ in glioblastomas

Sung Hugh Choi, Daniel W. Stuckey, Sara Pignatta, Clemens Reinshagen, Jasneet Kaur Khalsa, Nicolaas Roozendaal, Jordi Martinez-Quintanilla, Kaoru Tamura, Erhan Keles, Khalid Shah

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)7047-7058
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number22
DOIs
Publication statusPublished - Nov 15 2017

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Glioblastoma
Stem Cells
T-Lymphocytes
Neoplasms
Therapeutics
Cell Cycle Checkpoints
Cytokines
Mesenchymal Stromal Cells
Heterografts
Immunotherapy
Immune System
Patient Care
Research Design
Apoptosis
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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 journalArticle

Choi, SH, Stuckey, DW, Pignatta, S, Reinshagen, C, Khalsa, JK, Roozendaal, N, Martinez-Quintanilla, J, Tamura, K, Keles, E & Shah, K 2017, 'Tumor resection recruits effector T cells and boosts therapeutic efficacy of encapsulated stem cells expressing IFNβ in glioblastomas', Clinical Cancer Research, vol. 23, no. 22, pp. 7047-7058. https://doi.org/10.1158/1078-0432.CCR-17-0077
Choi, Sung Hugh ; Stuckey, Daniel W. ; Pignatta, Sara ; Reinshagen, Clemens ; Khalsa, Jasneet Kaur ; Roozendaal, Nicolaas ; Martinez-Quintanilla, Jordi ; Tamura, Kaoru ; Keles, Erhan ; Shah, Khalid. / Tumor resection recruits effector T cells and boosts therapeutic efficacy of encapsulated stem cells expressing IFNβ in glioblastomas. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 22. pp. 7047-7058.
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