Tumor Resection Recruits Effector T Cells and Boosts Therapeutic Efficacy of Encapsulated Stem Cells Expressing IFNβ in Glioblastomas

Abstract

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. 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. 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. 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. .

Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

“…Another point is that potential gene mutation-based alteration of spatial identity throughout the evolutionary process, as well as throughout growth of our models, was not evaluated in this study, thus the importance of specific genes and transcriptional regulators remains an open question. Additionally, given that surgical resection evokes a characteristic peritumoral immune response in the tumor microenvironment 44 , it will be an important area of future investigation to explore the interaction of edge tumor cells and post surgical infiltration of immune cells. Nonetheless, via utilization of these models, the identification of cell-intrinsic and microenvironmental regulators determining spatial identity should be possible and represents a critical step for development of edge-targeting therapy in GBM, with potential therapeutic benefit in other spatially heterogenous cancers.…”

Immune phenotyping of diverse syngeneic murine brain tumors identifies immunologically distinct types

“…Tissue processing for CyTOF. Mouse tumor samples were processed as previously described 22 . Briefly, right half of the brain was separated and minced with a scalpel on ice in calcium containing 1× HBSS (GIBCO) supplemented with 1 mg/ml Collagenase IV (Sigma) and 0.25 mg/ml DNase I (Sigma) and incubated for 1 h with intermittent shaking at 37°C.…”

“…Comprehensive immune profiling is done with CyTOF. Clinically, initial treatment for GBM patients is often resection, which as an intervention, is immunogenic resulting in an increase in tumor infiltrating immune cells (TIICs) in mouse GBM models 22,23 . In this study, we test the influence of resection on immune response, by performing immune profiling of tumors by CyTOF on pre-and post-resected tumors.…”

p19Arf sensitizes B16 melanoma cells to interferon-β delivered via mesenchymal stem cells in vitro

“…The transient nature of the technology should be sufficient to bring about cell killing and stimulation of an anti-tumor immune response. Though this point remains to be shown experimentally in our model, such responses have been reported (25)(26)(27)(28)(29). In addition, unresolved type I interferon signaling may actually be detrimental since it may induce immunosuppression (1), thus limiting the exposure to IFNb may be beneficial.…”