Broad immunophenotyping of the murine brain tumor microenvironment

Abstract Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.

Download Full-text

Distinct Tumor Microenvironment at Tumor Edge as a Result of Astrocyte Activation Is Associated With Therapeutic Resistance for Brain Tumor

Frontiers in Oncology ◽

10.3389/fonc.2019.00307 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Chiu-Min Lin ◽

Ching-Fang Yu ◽

Hsueh-Ya Huang ◽

Fang-Hsin Chen ◽

Ji-Hong Hong ◽

...

Keyword(s):

Brain Tumor ◽

Tumor Microenvironment ◽

Therapeutic Resistance ◽

Astrocyte Activation ◽

Tumor Edge

Download Full-text

TMIC-56. ROLE OF HUMAN BRAIN TUMOR STEM CELLS-DERIVED EXTRACELLULAR VESICLES ON THE PHENOTYPIC TRANSDIFFERENTIATION OF HUMAN NEURAL PROGENITOR CELLS

Neuro-Oncology ◽

10.1093/neuonc/noz175.1090 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi260-vi260

Author(s):

Natanael Zarco ◽

Emily Norton ◽

Montserrat Lara-Velazquez ◽

Anna Carrano ◽

Alfredo Quinones-Hinojosa ◽

...

Keyword(s):

Stem Cells ◽

Brain Tumor ◽

Tumor Microenvironment ◽

Extracellular Vesicles ◽

Primary Cultures ◽

Adult Brain ◽

Cell Subpopulation ◽

Tumor Stem Cells ◽

Brain Tumor Stem Cells

Abstract Glioblastoma (GBM) is the most aggressive of all the brain tumors with a median patient survival less than 15 months. Despite of surgical resection, radiotherapy, and chemotherapy, recurrence rate is almost 100%. A great percentage of GBM tumors (~60%) infiltrate and contact the ventricular-subventricular zone (V-SVZ). Interestingly, these tumors are the most aggressive, and invariably lead to higher distal recurrence rates, shorter time to tumor progression, and lower overall survival of the patient. The reason for this role of V-SVZ-proximity on the outcome of GBM patients is unknown. We suggest that a potential explanation is the interaction of GBM with the V-SVZ. This region is the largest neurogenic niche in the adult brain where neural stem cells (NSCs) give rise to newborn neuroblasts that migrate toward the olfactory bulb. In GBM there is a cell subpopulation called brain tumor stem cells (BTSCs) with NSCs-like characteristics, but with added potential for tumor initiation, recurrence and invasiveness. Tumor microenvironment plays an important role in migration and invasion process. In the present work, we used the total exosome isolation kit to purify Extracellular Vesicles (EVs) from human primary cultures of BTSCs. We determined that BTSCs-derived EVs contain specific information that is transfer to primary cultures of human Neural Progenitors Cells (NPCs) modulating their proliferation rate, cell viability, and migration. In addition, we identify that NPCs taken up BTSCs-derived EVs and significantly increase the expression levels of stemness-related genes such as Nestin, Nanog, and Sox2, suggesting that a phenotypic transdifferentiation is being carry out. These results support our hypothesis that GBM modulate the tumor microenvironment close to the V-SVZ by releasing EVs that target cellular components in this region and promote their phenotypic transformation, highlighting that NPCs biology changes in the context of tumor environment.

Download Full-text

IMMU-39. RNA LOADED LIPID-NANOPARTICLES FUNCTION AS CUSTOMIZABLE IMMUNOTHERAPEUTIC VEHICLES AGAINST MALIGNANT GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noz175.531 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi127-vi127

Author(s):

Adam Grippin ◽

Brandon Wummer ◽

Hector Mendez-Gomez ◽

Brian Stover ◽

Jianping Huang ◽

...

Keyword(s):

Brain Tumor ◽

Tumor Microenvironment ◽

Immune Cells ◽

Lipid Nanoparticles ◽

Lymphoid Organs ◽

Innate Immune ◽

T Cell Immunity ◽

Innate Immune Cells ◽

Cell Immunity ◽

The Brain

Abstract BACKGROUND While dendritic cell (DC) vaccine therapy has shown considerable promise for glioblastoma (GBM) patients (Mitchell et al. Nature, 2015), their advancement into human clinical trials has been fraught with challenges in the development, manufacturing, and marketing of successful cancer immunotherapies. To circumvent the challenges associated with cell therapy, we have developed a new platform technology consisting of tumor derived mRNA complexed into lipid-nanoparticles (RNA-NPs) for systemic delivery to DCs in vivo and induction of antigen specific T cell immunity against GBM. OBJECTIVES/ METHODS We sought to assess if surface and charge modifications to our custom lipid-NP could facilitate its localization to lymphoid organs and the brain tumor microenvironment. RESULTS We demonstrate that intravenous administration of our unmodified custom RNA-NPs mediate systemic activation of DCs; these include activation of CD11c+ cells in the brains of animals with intact blood brain-barriers (BBBs). RNA-NPs mediate antigen specific T cell immunity and anti-tumor efficacy with increased tumor infiltrating lymphocytes against a NF-1/p53 mutant glioma that recapitulates features of human GBM in immunocompetent mice. Modification of surface charge could direct these RNA-NPs to lymphoid organs (e.g. spleen, lymph nodes) while modification of the lipid backbone (with cholesterol) enhances localization to innate immune cells in NF-1/p53 mutant and GL261 gliomas. We therefore assessed if this customizable lipid-NP could be leveraged for delivery of immune checkpoint inhibitors (ICIs) (i.e. PD-L1 siRNA) to the brain tumor microenvironment. Compared with scrambled siRNA-NPs in combination with ICIs, surface modified siRNA-NPs (antagonizing PD-L1) in combination with ICIs mediated significant antitumor efficacy with 37% long term survivors in an otherwise fatal brain tumor model. CONCLUSION We designed multifunctional RNA-NPs with a simple, scalable synthesis method that enables delivery of nucleic acids to innate immune cells in lymphoid organs and brain tumors.

Download Full-text

Immunotherapy for Brain Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2017.72.8089 ◽

2017 ◽

Vol 35 (21) ◽

pp. 2450-2456 ◽

Cited By ~ 47

Author(s):

John H. Sampson ◽

Marcela V. Maus ◽

Carl H. June

Keyword(s):

Brain Tumor ◽

Tumor Microenvironment ◽

Brain Tumors ◽

Imaging Technologies ◽

Cellular Therapies ◽

New Approaches ◽

Recent Advances ◽

Medical Need

Glioblastoma (GBM) is the most lethal form of brain tumor and remains a large, unmet medical need. This review focuses on recent advances in the neurosciences that converge with the broader field of immuno-oncology. Recent findings in neuroanatomy provide a basis for new approaches of cellular therapies for tumors that involve the CNS. The ultimate success of immunotherapy in the CNS will require improved imaging technologies and methods for analysis of the tumor microenvironment in patients with GBM. It is likely that combinatorial approaches with targeted immunotherapies will be required to exploit the vulnerabilities of GBM and other brain tumors.

Download Full-text