المؤلفون: Takayuki Ohkuri, Akemi Kosaka, Hideho Okada, Maki Ikeura, Andres M Salazar

المصدر: Journal for ImmunoTherapy of Cancer, Vol 9, Iss 6 (2021)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Background While adoptive transfer of T-cells has been a major medical breakthrough for patients with B cell malignancies, the development of safe and effective T-cell-based immunotherapy for central nervous system (CNS) tumors, such as glioblastoma (GBM), still needs to overcome multiple challenges, including effective homing and persistence of T-cells. Based on previous observations that interleukin (IL)-17-producing T-cells can traffic to the CNS in autoimmune conditions, we evaluated CD8+ T-cells that produce IL-17 and interferon-γ (IFN-γ) (Tc17-1) cells in a preclinical GBM model.Methods We differentiated Pmel-1 CD8+ T-cells into Tc17-1 cells and compared their phenotypic and functional characteristics with those of IFN-γ-producing CD8+ T (Tc1) and IL-17-producing CD8+ T (Tc17) cells. We also evaluated the therapeutic efficacy, persistence, and tumor-homing of Tc17-1 cells in comparison to Tc1 cells using a mouse GL261 glioma model.Results In vitro, Tc17-1 cells demonstrated profiles of both Tc1 and Tc17 cells, including production of both IFN-γ and IL-17, although Tc17-1 cells demonstrated lesser degrees of antigen-specific cytotoxic activity compared with Tc1 cells. In mice-bearing intracranial GL261-Quad tumor and treated with temozolomide, Tc1 cells, but not Tc17-1, showed a significant prolongation of survival. However, when the T-cell transfer was combined with poly-ICLC and Pmel-1 peptide vaccine, both Tc1 and Tc17-1 cells exhibited significantly prolonged survival associated with upregulation of very late activation antigen−4 on Tc17-1 cells in vivo. Glioma cells that recurred following the therapy lost the susceptibility to Pmel-1-derived cytotoxic T-cells, indicating that immuno-editing was a mechanism of the acquired resistance.Conclusions Tc17-1 cells were equally effective as Tc1 cells when combined with poly-ICLC and peptide vaccine treatment.

وصف الملف: electronic resource

العلاقة: https://jitc.bmj.com/content/9/6/e002426.fullTest; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/307005996c904b799e987fa00e75d74dTest

المؤلفون: Laura Pinton, Elena Masetto, Marina Vettore, Samantha Solito, Sara Magri, Marta D’Andolfi, Paola Del Bianco, Giovanna Lollo, Jean-Pierre Benoit, Hideho Okada, Aaron Diaz, Alessandro Della Puppa, Susanna Mandruzzato

المصدر: Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-14 (2019)

مصطلحات موضوعية: Innate immunity, Tumor microenvironment, Tumor immunology, Immunological tolerance, Brain cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Systemic and local immune suppression plays a significant role in glioma progression. Glioma microenvironment contains both brain-resident microglial cells (MG) and bone marrow-derived macrophages (BMDM), but the study of their functional and immune regulatory activity has been hampered until now by the lack of markers allowing a proper identification and isolation to collect pure populations. Methods Myeloid and lymphoid infiltrate were characterized in grade II, III and IV gliomas by multicolor flow cytometry, along with the composition of the cell subsets of circulating myeloid cells. Macrophages were sorted and tested for their immunosuppressive ability. Moreover, following preoperative administration of 5-aminolevulinic acid to patients, distinct areas of tumor lesion were surgically removed and analyzed, based on protoporphyrin IX fluorescence emission. Results The immune microenvironment of grade II to grade IV gliomas contains a large proportion of myeloid cells and a small proportion of lymphocytes expressing markers of dysfunctional activity. BMDM and resident MG cells were characterized through a combination of markers, thus permitting their geographical identification in the lesions, their sorting and subsequent analysis of the functional characteristics. The infiltration by BMDM reached the highest percentages in grade IV gliomas, and it increased from the periphery to the center of the lesion, where it exerted a strong immunosuppression that was, instead, absent in the marginal area. By contrast, MG showed little or no suppression. Functional differences, such as iron metabolism and phagocytosis, characterized resident versus blood-derived macrophages. Significant alterations in circulating monocytes were present in grade IV patients, correlating with accumulation of tumor macrophages. Conclusions Grade IV gliomas have an alteration in both circulating and tumor-associated myeloid cells and, differently from grade II and III gliomas, show a significant presence of blood-derived, immune suppressive macrophages. BMDM and MG have different functional properties.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s40425-019-0536-xTest; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/c92e2118ef024d7281d5ce47a312ac6bTest

المؤلفون: Sharmila Nair, Luciano Mazzoccoli, Arijita Jash, Jennifer Govero, Sachendra S. Bais, Tong Hu, Camila R. Fontes-Garfias, Chao Shan, Hideho Okada, Sujan Shresta, Jeremy N. Rich, Pei-Yong Shi, Michael S. Diamond, Milan G. Chheda

المصدر: JCI Insight, Vol 6, Iss 1 (2021)

مصطلحات موضوعية: Immunology, Oncology, Medicine

الوصف: Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increased recruitment of CD8+ T and myeloid cells to the tumor microenvironment. CD8+ T cells were required for ZIKV-dependent tumor clearance because survival benefits were lost with CD8+ T cell depletion. Moreover, while anti–PD-1 antibody monotherapy moderately improved tumor survival, when coadministered with ZIKV, survival increased. ZIKV-mediated tumor clearance also resulted in durable protection against syngeneic tumor rechallenge, which also depended on CD8+ T cells. To address safety concerns, we generated an immune-sensitized ZIKV strain, which was effective alone or in combination with immunotherapy. Thus, oncolytic ZIKV treatment can be leveraged by immunotherapies, which may prompt combination treatment paradigms for adult patients with GBM.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2379-3708Test

الوصول الحر: https://doaj.org/article/cc0774b684754a278d9b7e4db97ef179Test

المؤلفون: Sören Müller, Gary Kohanbash, S. John Liu, Beatriz Alvarado, Diego Carrera, Aparna Bhaduri, Payal B. Watchmaker, Garima Yagnik, Elizabeth Di Lullo, Martina Malatesta, Nduka M. Amankulor, Arnold R. Kriegstein, Daniel A. Lim, Manish Aghi, Hideho Okada, Aaron Diaz

المصدر: Genome Biology, Vol 18, Iss 1, Pp 1-14 (2017)

مصطلحات موضوعية: Glioma, Single-cell sequencing, Immunotherapy, Macrophage, Biology (General), QH301-705.5, Genetics, QH426-470

الوصف: Abstract Background Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue. Results We perform single-cell RNA-sequencing of human gliomas and identify phenotypic differences in TAMs of distinct lineages. We isolate TAMs from patient biopsies and compare them with macrophages from non-malignant human tissue, glioma atlases, and murine glioma models. We present a novel signature that distinguishes TAMs by ontogeny in human gliomas. Blood-derived TAMs upregulate immunosuppressive cytokines and show an altered metabolism compared to microglial TAMs. They are also enriched in perivascular and necrotic regions. The gene signature of blood-derived TAMs, but not microglial TAMs, correlates with significantly inferior survival in low-grade glioma. Surprisingly, TAMs frequently co-express canonical pro-inflammatory (M1) and alternatively activated (M2) genes in individual cells. Conclusions We conclude that blood-derived TAMs significantly infiltrate pre-treatment gliomas, to a degree that varies by glioma subtype and tumor compartment. Blood-derived TAMs do not universally conform to the phenotype of microglia, but preferentially express immunosuppressive cytokines and show an altered metabolism. Our results argue against status quo therapeutic strategies that target TAMs indiscriminately and in favor of strategies that specifically target immunosuppressive blood-derived TAMs.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s13059-017-1362-4Test; https://doaj.org/toc/1474-760XTest

الوصول الحر: https://doaj.org/article/b3ec0e0d5c1c43f3ad2d248d295ddd67Test

المؤلفون: Pavlina Chuntova, Kira M. Downey, Bindu Hegde, Neil D. Almeida, Hideho Okada

المصدر: Frontiers in Immunology, Vol 9 (2019)

مصطلحات موضوعية: T lymphocyte, brain cancer, Glioblastoma, TCR - T cell receptor, CAR (chimeric antigen receptor) T cells, Glioma, Immunologic diseases. Allergy, RC581-607

الوصف: Malignant gliomas carry a dismal prognosis. Conventional treatment using chemo- and radiotherapy has limited efficacy with adverse events. Therapy with genetically engineered T-cells, such as chimeric antigen receptor (CAR) T-cells, may represent a promising approach to improve patient outcomes owing to their potential ability to attack highly infiltrative tumors in a tumor-specific manner and possible persistence of the adaptive immune response. However, the unique anatomical features of the brain and susceptibility of this organ to irreversible tissue damage have made immunotherapy especially challenging in the setting of glioma. With safety concerns in mind, multiple teams have initiated clinical trials using CAR T-cells in glioma patients. The valuable lessons learnt from those trials highlight critical areas for further improvement: tackling the issues of the antigen presentation and T-cell homing in the brain, immunosuppression in the glioma microenvironment, antigen heterogeneity and off-tumor toxicity, and the adaptation of existing clinical therapies to reflect the intricacies of immune response in the brain. This review summarizes the up-to-date clinical outcomes of CAR T-cell clinical trials in glioma patients and examines the most pressing hurdles limiting the efficacy of these therapies. Furthermore, this review uses these hurdles as a framework upon which to evaluate cutting-edge pre-clinical strategies aiming to overcome those barriers.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/article/10.3389/fimmu.2018.03062/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/b48ab0099be343549d9ff375a177666aTest

المؤلفون: Vassilis Genoud, Eliana Marinari, Sergey I Nikolaev, John C. Castle, Valesca Bukur, Pierre-Yves Dietrich, Hideho Okada, Paul R. Walker

المصدر: OncoImmunology, Vol 7, Iss 12 (2018)

مصطلحات موضوعية: immune checkpoint blockade, glioblastoma, gl261, sb28, mutational load, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Immune checkpoint blockade (ICB) is currently evaluated in patients with glioblastoma (GBM), based on encouraging clinical data in other cancers, and results from studies with the methylcholanthrene-induced GL261 mouse glioma. In this paper, we describe a novel model faithfully recapitulating some key human GBM characteristics, including low mutational load, a factor reported as a prognostic indicator of ICB response. Consistent with this observation, SB28 is completely resistant to ICB, contrasting with treatment sensitivity of the more highly mutated GL261. Moreover, SB28 shows features of a poorly immunogenic tumor, with low MHC-I expression and modest CD8+ T-cell infiltration, suggesting that it may present similar challenges for immunotherapy as human GBM. Based on these key features for immune reactivity, SB28 may represent a treatment-resistant malignancy likely to mirror responses of many human tumors. We therefore propose that SB28 is a particularly suitable model for optimization of GBM immunotherapy.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2162-402XTest

الوصول الحر: https://doaj.org/article/ff0f1c46268643f284c500382f723d44Test

المؤلفون: Valérie Dutoit, Denis Migliorini, Giulia Ranzanici, Eliana Marinari, Valérie Widmer, Johannes Alexander Lobrinus, Shahan Momjian, Joseph Costello, Paul R. Walker, Hideho Okada, Toni Weinschenk, Christel Herold-Mende, Pierre-Yves Dietrich

المصدر: OncoImmunology, Vol 7, Iss 2 (2018)

مصطلحات موضوعية: grade ii glioma, grade iii glioma, immunotherapy, peptide vaccine, ima950, spontaneous t cell responses, astrocytoma, oligodendroglioma, ependymoma, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Gliomas are lethal brain tumors that resist standard therapeutic approaches. Immunotherapy is a promising alternative strategy mostly developed in the context of glioblastoma. However, there is a need for implementing immunotherapy for grade II/III gliomas, as these are the most common CNS tumors in young adults with a high propensity for recurrence, making them lethal despite current treatments. We recently identified HLA-A2-restricted tumor-associated antigens by peptide elution from glioblastoma and formulated a multipeptide vaccine (IMA950) evaluated in phase I/II clinical trials with promising results. Here, we investigated expression of the IMA950 antigens in patients with grade II/III astrocytoma, oligodendroglioma or ependymoma, at the mRNA, protein and peptide levels. We report that the BCAN, CSPG4, IGF2BP3, PTPRZ1 and TNC proteins are significantly over-expressed at the mRNA (n = 159) and protein (n = 36) levels in grade II/III glioma patients as compared to non-tumor samples (IGF2BP3 being absent from oligodendroglioma). Most importantly, we detected spontaneous antigen-specific T cell responses to one or more of the IMA950 antigens in 100% and 71% of grade II and grade III patients, respectively (27 patients tested). These patients displayed T cell responses of better quality (higher frequency, broader epitope targeting) than patients with glioblastoma. Detection of spontaneous T cell responses to the IMA950 antigens shows that these antigens are relevant for tumor targeting, which will be best achieved by combination with CD4 epitopes such as the IDH1R132H peptide. Altogether, we provide the rationale for using a selective set of IMA950 peptides for vaccination of patients with grade II/III glioma.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2162-402XTest

الوصول الحر: https://doaj.org/article/091305975d084e2fad510b8cdbfb2201Test

المؤلفون: Brian J. Ahn, Ian F. Pollack, Hideho Okada

المصدر: Cancers, Vol 5, Iss 4, Pp 1379-1412 (2013)

مصطلحات موضوعية: glioma, cancer vaccines, tumor immunity, T cells, tumor microenvironment, cancer immunotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

وصف الملف: electronic resource

العلاقة: http://www.mdpi.com/2072-6694/5/4/1379Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/22a6584637e941b0a07f942beba0916cTest

المؤلفون: Manabu Hatano, Junichi Eguchi, Tomohide Tatsumi, Naruo Kuwashima, Jill E. Dusak, Michel S. Kinch, Ian F. Pollack, Ronald L. Hamilton, Walter J. Storkus, Hideho Okada

المصدر: Neoplasia: An International Journal for Oncology Research, Vol 7, Iss 8, Pp 717-722 (2005)

مصطلحات موضوعية: EphA2, glioma, cancer vaccine, cytotoxic T lymphocytes, human leukocyte antigen (HLA) A2, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: EphA2 is a receptor tyrosine kinase, is frequently overexpressed in a wide array of advanced cancers. We demonstrate in the current study that the EphA2 protein is restrictedly expressed in primary glioblastoma multiforme, anaplastic astrocytoma tissues in comparison to normal brain tissues. To evaluate the possibility of targeting EphA2 in glioma vaccine strategies, we stimulated human leukocyte antigen (HLA) A2+ peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, glioma patients with autologous dendritic cells (DCs) loaded with synthetic EphA2$$3_$91 peptide (TLADFDPRV), which has previously been reported to induce interferon-δ in HLAA2+ PBMCs. Stimulated PBMCs demonstrated antigenspecific cytotoxic T lymphocyte (CTL) responses as detected by specific lysis of T2 cells loaded with the EphA2883 peptide as well as HLA-A2+ glioma cells, SNB19, U251, that express EphA2. Furthermore, in vivo immunization of HLA-A2 transgenic HHD mice with the EphA2883-891 peptide resulted in the development of an epitope-specific CTL response in splenocytes, despite the fact that EphA2883-891 is an autoantigen in these mice. Taken together, these data suggest that EphA2883-891 may be an attractive antigen epitope for molecularly targeted glioma vaccines.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S1476558605801034Test; https://doaj.org/toc/1476-5586Test; https://doaj.org/toc/1522-8002Test

الوصول الحر: https://doaj.org/article/ed476c37733343d7aaa8f27f59a8dcdaTest

المؤلفون: Jia Zhong, Masashi Sakaki, Hideho Okada, Eric T Ahrens

المصدر: PLoS ONE, Vol 8, Iss 5, p e59479 (2013)

مصطلحات موضوعية: Medicine, Science

الوصف: Noninvasive biomarkers of anti-tumoral efficacy are of great importance to the development of therapeutic agents. Tumor oxygenation has been shown to be an important indicator of therapeutic response. We report the use of intracellular labeling of tumor cells with perfluorocarbon (PFC) molecules, combined with quantitative ¹⁹F spin-lattice relaxation rate (R₁) measurements, to assay tumor cell oxygen dynamics in situ. In a murine central nervous system (CNS) GL261 glioma model, we visualized the impact of Pmel-1 cytotoxic T cell immunotherapy, delivered intravenously, on intracellular tumor oxygen levels. GL261 glioma cells were labeled ex vivo with PFC and inoculated into the mouse striatum. The R₁ of ¹⁹F labeled cells was measured using localized single-voxel magnetic resonance spectroscopy, and the absolute intracellular partial pressure of oxygen (pO₂) was ascertained. Three days after tumor implantation, mice were treated with 2×10⁷ cytotoxic T cells intravenously. At day five, a transient spike in pO₂ was observed indicating an influx of T cells into the CNS and putative tumor cell apoptosis. Immunohistochemistry and quantitative flow cytometry analysis confirmed that the pO₂ was causally related to the T cells infiltration. Surprisingly, the pO₂ spike was detected even though few (∼4×10⁴) T cells actually ingress into the CNS and with minimal tumor shrinkage. These results indicate the high sensitivity of this approach and its utility as a non-invasive surrogate biomarker of anti-cancer immunotherapeutic response in preclinical models.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3648573?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/7ed99c5123a846339859cc57347e69ecTest