bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023‒05‒14
fifteen papers selected by
Oltea Sampetrean
Keio University
  1. Glioma immunotherapy enhancement and CD8-specific sialic acid cleavage by isocitrate dehydrogenase (IDH)-1.
  2. Antisense oligonucleotide slows glioma growth.
  3. Glioblastoma Rewires Neural Circuits That Impair Cognition and Survival.
  4. Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators.
  5. Structural gray matter alterations in glioblastoma and high-grade glioma-A potential biomarker of survival.
  6. Recruitment mechanisms and therapeutic implications of tumor-associated macrophages in the glioma microenvironment.
  7. A single-institution retrospective analysis of pathologically determined malignant transformation in IDH mutant glioma patients.
  8. GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.
  9. Integrated analysis of single-cell chromatin state and transcriptome identified common vulnerability despite glioblastoma heterogeneity.
  10. Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin.
  11. Pediatric diffuse midline glioma: Understanding the mechanisms and assessing the next generation of personalized therapeutics.
  12. HER2 chimeric antigen receptor T cell immunotherapy is an effective treatment for diffuse intrinsic pontine glioma.
  13. TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma.
  14. Intracranial injection of NK cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma.
  15. TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma.
  1. Oncogene. 2023 May 09.
    Glioma immunotherapy enhancement and CD8-specific sialic acid cleavage by isocitrate dehydrogenase (IDH)-1.
    Ryan Cordner, Michelle Jhun, Akanksha Panwar, HongQiang Wang, Nicole Gull, Ramachandran Murali, Joseph H McAbee, Armen Mardiros, Akane Sanchez-Takei, Mia W Mazer, Xuemo Fan, Emmanuel Jouanneau, John S Yu, Keith L Black, Christopher J Wheeler.
      The promise of adaptive cancer immunotherapy in treating highly malignant tumors such as glioblastoma multiforme (GBM) can only be realized through expanding its benefits to more patients. Alleviating various modes of immune suppression has so far failed to achieve such expansion, but exploiting endogenous immune enhancers among mutated cancer genes could represent a more direct approach to immunotherapy improvement. We found that Isocitrate Dehydrogenase-1 (IDH1), which is commonly mutated in gliomas, enhances glioma vaccine efficacy in mice and discerns long from short survivors after vaccine therapy in GBM patients. Extracellular IDH1 directly enhanced T cell responses to multiple tumor antigens, and prolonged experimental glioma cell lysis. Moreover, IDH1 specifically bound to and exhibited sialidase activity against CD8. By contrast, mutant IDH1R132H lacked sialidase activity, delayed killing in glioma cells, and decreased host survival after immunotherapy. Overall, our findings identify IDH1 as an immunotherapeutic enhancer that mediates the known T cell-enhancing reaction of CD8 desialylation. This uncovers a new axis for immunotherapeutic improvement in GBM and other cancers, reveals novel physiological and molecular functions of IDH1, and hints at an unexpectedly direct link between lytic T cell function and metabolic activity in target cells.
    DOI:  https://doi.org/10.1038/s41388-023-02713-7
  2. Nat Rev Drug Discov. 2023 May 10.
    Antisense oligonucleotide slows glioma growth.
    Caroline Barranco.
      
    DOI:  https://doi.org/10.1038/d41573-023-00077-x
  3. Cancer Discov. 2023 May 12. OF1
    Glioblastoma Rewires Neural Circuits That Impair Cognition and Survival.
      Glioblastomas remodel neural circuits such that task-relevant neural responses promote tumor growth.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-071
  4. Acta Neuropathol Commun. 2023 May 10. 11(1): 79
    Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators.
    Berta Segura-Collar, Sara Hiller-Vallina, Olaya de Dios, Marta Caamaño-Moreno, Lucia Mondejar-Ruescas, Juan M Sepulveda-Sanchez, Ricardo Gargini.
      Glial-origin brain tumors, including glioblastomas (GBM), have one of the worst prognoses due to their rapid and fatal progression. From an oncological point of view, advances in complete surgical resection fail to eliminate the entire tumor and the remaining cells allow a rapid recurrence, which does not respond to traditional therapeutic treatments. Here, we have reviewed new immunotherapy strategies in association with the knowledge of the immune micro-environment. To understand the best lines for the future, we address the advances in the design of neoantigen vaccines and possible new immune modulators. Recently, the efficacy and availability of vaccine development with different formulations, especially liposome plus mRNA vaccines, has been observed. We believe that the application of new strategies used with mRNA vaccines in combination with personalized medicine (guided by different omic's strategies) could give good results in glioma therapy. In addition, a large part of the possible advances in new immunotherapy strategies focused on GBM may be key improving current therapies of immune checkpoint inhibitors (ICI), given the fact that this type of tumor has been highly refractory to ICI.
    Keywords:  Glioblastoma; Glioma; Immune checkpoint inhibitors; Immunotherapy; Neoantigen vaccine; PD-1; PD-L1; Suppressive myeloid cells; Tumor microenvironment; Virotherapy; mRNA vaccine
    DOI:  https://doi.org/10.1186/s40478-023-01569-y
  5. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad034
    Structural gray matter alterations in glioblastoma and high-grade glioma-A potential biomarker of survival.
    Bidhan Lamichhane, Patrick H Luckett, Donna Dierker, Ki Yun Park, Harold Burton, Michael Olufawo, Gabriel Trevino, John J Lee, Andy G S Daniel, Carl D Hacker, Daniel S Marcus, Joshua S Shimony, Eric C Leuthardt.
      Background: Patients with glioblastoma (GBM) and high-grade glioma (HGG, World Health Organization [WHO] grade IV glioma) have a poor prognosis. Consequently, there is an unmet clinical need for accessible and noninvasively acquired predictive biomarkers of overall survival in patients. This study evaluated morphological changes in the brain separated from the tumor invasion site (ie, contralateral hemisphere). Specifically, we examined the prognostic value of widespread alterations of cortical thickness (CT) in GBM/HGG patients.Methods: We used FreeSurfer, applied with high-resolution T1-weighted MRI, to examine CT, evaluated prior to standard treatment with surgery and chemoradiation in patients (GBM/HGG, N = 162, mean age 61.3 years) and 127 healthy controls (HC; 61.9 years mean age). We then compared CT in patients to HC and studied patients' associated changes in CT as a potential biomarker of overall survival.
    Results: Compared to HC cases, patients had thinner gray matter in the contralesional hemisphere at the time of tumor diagnosis. patients had significant cortical thinning in parietal, temporal, and occipital lobes. Fourteen cortical parcels showed reduced CT, whereas in 5, it was thicker in patients' cases. Notably, CT in the contralesional hemisphere, various lobes, and parcels was predictive of overall survival. A machine learning classification algorithm showed that CT could differentiate short- and long-term survival patients with an accuracy of 83.3%.
    Conclusions: These findings identify previously unnoticed structural changes in the cortex located in the hemisphere contralateral to the primary tumor mass. Observed changes in CT may have prognostic value, which could influence care and treatment planning for individual patients.
    Keywords:  biomarker of GBM and HGG; brain tumor; cortical thickness; glioblastoma and high-grade glioma; overall survival
    DOI:  https://doi.org/10.1093/noajnl/vdad034
  6. Front Immunol. 2023 ;14 1067641
    Recruitment mechanisms and therapeutic implications of tumor-associated macrophages in the glioma microenvironment.
    Xianzhe Zhou, Guishan Jin, Junwen Zhang, Fusheng Liu.
      As one of the main components of the glioma immune microenvironment, glioma-associated macrophages (GAMs) have increasingly drawn research interest. Primarily comprised of resident microglias and peripherally derived mononuclear macrophages, GAMs are influential in a variety of activities such as tumor cell resistance to chemotherapy and radiotherapy as well as facilitation of glioma pathogenesis. In addition to in-depth research of GAM polarization, study of mechanisms relevant in tumor microenvironment recruitment has gradually increased. Suppression of GAMs at their source is likely to produce superior therapeutic outcomes. Here, we summarize the origin and recruitment mechanism of GAMs, as well as the therapeutic implications of GAM inhibition, to facilitate future glioma-related research and formulation of more effective treatment strategies.
    Keywords:  cytokine; glioma; glioma-associated microglia/macrophages; recruitment of macrophages; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1067641
  7. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad036
    A single-institution retrospective analysis of pathologically determined malignant transformation in IDH mutant glioma patients.
    Vicki Liu, Ethan A Wetzel, Blaine S C Eldred, Serendipity Zapanta Rinonos, Terry J Prins, Negar Khanlou, Linda M Liau, Robert Chong, Phioanh L Nghiemphu, Timothy F Cloughesy, Benjamin M Ellingson, Albert Lai.
      Background: Lower-grade IDH mutant glioma patients frequently undergo malignant transformation (MT), with apparent worse prognosis. Many studies examine MT in mixed IDH status cohorts and define MT using imaging, not histopathology. Our study examines the timing, predictors, and prognostic implications of pathologically determined MT in a large, exclusively IDH mutant cohort.Methods: We identified 193 IDH mutant lower-grade glioma patients at UCLA who received multiple surgeries. We examined the outcomes of pathologically determined MT patients.
    Results: Time to MT is longer in grade 2 oligodendroglioma (G2 Oligo) than in grade 2 astrocytoma (G2 Astro) (HR = 0.46, P = .0007). The grade 3 astrocytoma (G3 Astro) to grade 4 astrocytoma (G4 Astro) interval is shorter in stepwise MT (G2 to G3 to G4 Astro) patients than in initial G3 Astro patients (P = .03). Novel contrast enhancement had 65% positive predictivity, 67% negative predictivity, 75% sensitivity, and 55% specificity in indicating pathologically defined MT. In G2 Astro, initial gross total resection delayed MT (HR = 0.50, P = .02) and predicted better overall survival (OS) (HR = 0.34, P = .009). In G2 Oligo, spontaneous MT occurred earlier than treated MT (HR = 11.43, P = .0002), but treatment did not predict improved OS (P = .8). MT patients (n = 126) exhibited worse OS than non-MT patients (n = 67) in All (HR = 2.54, P = .0009) and G2 Astro (HR = 4.26, P = .02).
    Conclusion: Our study expands the understanding of MT to improve IDH mutant lower-grade glioma management.
    Keywords:  IDH1/2; glioma; malignant transformation; progression; tumor grade
    DOI:  https://doi.org/10.1093/noajnl/vdad036
  8. Nat Cancer. 2023 May 11.
    GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.
    Dionysios C Watson, Defne Bayik, Simon Storevik, Shannon Sherwin Moreino, Samuel A Sprowls, Jianhua Han, Mina Thue Augustsson, Adam Lauko, Palavalasa Sravya, Gro Vatne Røsland, Katie Troike, Karl Johan Tronstad, Sabrina Wang, Katharina Sarnow, Kristen Kay, Taral R Lunavat, Daniel J Silver, Sahil Dayal, Justin Vareecal Joseph, Erin Mulkearns-Hubert, Lars Andreas Rømo Ystaas, Gauravi Deshpande, Joris Guyon, Yadi Zhou, Capucine R Magaut, Juliana Seder, Laura Neises, Sarah E Williford, Johannes Meiser, Andrew J Scott, Peter Sajjakulnukit, Jason A Mears, Rolf Bjerkvig, Abhishek Chakraborty, Thomas Daubon, Feixiong Cheng, Costas A Lyssiotis, Daniel R Wahl, Anita B Hjelmeland, Jubayer A Hossain, Hrvoje Miletic, Justin D Lathia.
      The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host-tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development.
    DOI:  https://doi.org/10.1038/s43018-023-00556-5
  9. Proc Natl Acad Sci U S A. 2023 05 16. 120(20): e2210991120
    Integrated analysis of single-cell chromatin state and transcriptome identified common vulnerability despite glioblastoma heterogeneity.
    Ramya Raviram, Anugraha Raman, Sebastian Preissl, Jiangfang Ning, Shaoping Wu, Tomoyuki Koga, Kai Zhang, Cameron W Brennan, Chenxu Zhu, Jens Luebeck, Kinsey Van Deynze, Jee Yun Han, Xiaomeng Hou, Zhen Ye, Anna K Mischel, Yang Eric Li, Rongxin Fang, Tomas Baback, Joshua Mugford, Claudia Z Han, Christopher K Glass, Cathy L Barr, Paul S Mischel, Vineet Bafna, Laure Escoubet, Bing Ren, Clark C Chen.
      In 2021, the World Health Organization reclassified glioblastoma, the most common form of adult brain cancer, into isocitrate dehydrogenase (IDH)-wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intratumoral heterogeneity is a key contributor to therapeutic failure. To better define this heterogeneity, genome-wide chromatin accessibility and transcription profiles of clinical samples of glioblastomas and G4 IDHm astrocytomas were analyzed at single-cell resolution. These profiles afforded resolution of intratumoral genetic heterogeneity, including delineation of cell-to-cell variations in distinct cell states, focal gene amplifications, as well as extrachromosomal circular DNAs. Despite differences in IDH mutation status and significant intratumoral heterogeneity, the profiled tumor cells shared a common chromatin structure defined by open regions enriched for nuclear factor 1 transcription factors (NFIA and NFIB). Silencing of NFIA or NFIB suppressed in vitro and in vivo growths of patient-derived glioblastomas and G4 IDHm astrocytoma models. These findings suggest that despite distinct genotypes and cell states, glioblastoma/G4 astrocytoma cells share dependency on core transcriptional programs, yielding an attractive platform for addressing therapeutic challenges associated with intratumoral heterogeneity.
    Keywords:  amplicons; extrachromosomal DNA; glioblastoma; single cell
    DOI:  https://doi.org/10.1073/pnas.2210991120
  10. Cell Rep. 2023 May 05. pii: S2211-1247(23)00483-7. [Epub ahead of print]42(5): 112472
    Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin.
    Claudia Garcia-Diaz, Anni Pöysti, Elisabetta Mereu, Melanie P Clements, Lucy J Brooks, Felipe Galvez-Cancino, Simon P Castillo, Wenhao Tang, Gordon Beattie, Lilas Courtot, Sara Ruiz, Federico Roncaroli, Yinyin Yuan, Samuel Marguerat, Sergio A Quezada, Holger Heyn, Simona Parrinello.
      Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these cells resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, to compare matched bulk and margin cells. We find that, regardless of mutations, tumors converge on common sets of neural-like cellular states. However, bulk and margin have distinct biology. Injury-like programs associated with immune infiltration dominate in the bulk, leading to the generation of lowly proliferative injured neural progenitor-like cells (iNPCs). iNPCs account for a significant proportion of dormant GBM cells and are induced by interferon signaling within T cell niches. In contrast, developmental-like trajectories are favored within the immune-cold margin microenvironment resulting in differentiation toward invasive astrocyte-like cells. These findings suggest that the regional tumor microenvironment dominantly controls GBM cell fate and biological vulnerabilities identified in the bulk may not extend to the margin residuum.
    Keywords:  CP: Cancer; dormancy; glioblastoma; invasion; somatic mouse models; tumor margin; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2023.112472
  11. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad040
    Pediatric diffuse midline glioma: Understanding the mechanisms and assessing the next generation of personalized therapeutics.
    Nicolina Jovanovich, Ahmed Habib, Jeffery Head, Farrukh Hameed, Sameer Agnihotri, Pascal O Zinn.
      Diffuse midline glioma (DMG) is a pediatric cancer that originates in the midline structures of the brain. Prognosis of DMG patients remains poor due to the infiltrative nature of these tumors and the protection they receive from systemically delivered therapeutics via an intact blood-brain barrier (BBB), making treatment difficult. While the cell of origin remains disputed, it is believed to reside in the ventral pons. Recent research has pointed toward epigenetic dysregulation inducing an OPC-like transcriptomic signature in DMG cells. This epigenetic dysregulation is typically caused by a mutation (K27M) in one of two histone genes-H3F3A or HIST1H3B -and can lead to a differentiation block that increases these cells oncogenic potential. Standard treatment with radiation is not sufficient at overcoming the aggressivity of this cancer and only confers a survival benefit of a few months, and thus, discovery of new therapeutics is of utmost importance. In this review, we discuss the cell of origin of DMGs, as well as the underlying molecular mechanisms that contribute to their aggressivity and resistance to treatment. Additionally, we outline the current standard of care for DMG patients and the potential future therapeutics for this cancer that are currently being tested in preclinical and clinical trials.
    Keywords:  Pontine; glioma; model; pediatric; therapeutics
    DOI:  https://doi.org/10.1093/noajnl/vdad040
  12. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad024
    HER2 chimeric antigen receptor T cell immunotherapy is an effective treatment for diffuse intrinsic pontine glioma.
    Stacie S Wang, Alexander J Davenport, Melinda Iliopoulos, Hannah E Hughes-Parry, Katherine A Watson, Valeria Arcucci, Matthias Mulazzani, David D Eisenstat, Jordan R Hansford, Ryan S Cross, Misty R Jenkins.
      Background: Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) of the thalamus and spinal cord are rare but devastating high-grade glial tumors of childhood with no curative treatment. Despite aggressive treatment attempts the prognosis has remained poor. Chimeric antigen receptor (CAR) T cell therapy has been identified as a promising new approach in the treatment of DMG tumors; however, additional targets are urgently required given known tumor heterogeneity and the prospect of antigen escape of this cancer.Methods: Using cell surface mass spectrometry, we detected high HER2 cell surface protein across a panel of patient-derived DIPG cells, thereby identifying an existing CAR T cell therapy for use in DIPG. Primary human T cells were transduced to express a second-generation HER2 CAR and interrogated for efficacy against patient-derived DIPG cells.
    Results: HER2 CAR T cells demonstrated potent and antigen-specific cytotoxicity and cytokine secretion when co-cultured with patient-derived DIPG cells. Furthermore, HER2 CAR T cells provided a significant regression in intracranial DIPG xenograft tumors.
    Conclusions: HER2 CAR T cells are already in clinic development and are well tolerated in pediatric patients. Here we provide strong preclinical evidence for the inclusion of DIPG patients in future pediatric CNS tumor HER2 CAR T cell clinical trials.
    Keywords:  Chimeric antigen receptor (CAR) T cells; diffuse intrinsic pontine glioma (DIPG); diffuse midline glioma (DMG); human epidermal growth factor receptor 2 (HER2); immunotherapy
    DOI:  https://doi.org/10.1093/noajnl/vdad024
  13. Sci Adv. 2023 May 12. 9(19): eade3559
    TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma.
    Rui Sun, Rowland Han, Colin McCornack, Saad Khan, G Travis Tabor, Yun Chen, Jinchao Hou, Haowu Jiang, Kathleen M Schoch, Diane D Mao, Ryan Cleary, Alicia Yang, Qin Liu, Jingqin Luo, Allegra Petti, Timothy M Miller, Jason D Ulrich, David M Holtzman, Albert H Kim.
      Triggering receptor expressed on myeloid cells 2 (TREM2) plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. Here, we found that TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in patients with GBM. TREM2 loss of function in human macrophages and mouse myeloid cells increased interferon-γ-induced immunoactivation, proinflammatory polarization, and tumoricidal capacity. In orthotopic mouse GBM models, mice with chronic and acute Trem2 loss of function exhibited decreased tumor growth and increased survival. Trem2 inhibition reprogrammed myeloid phenotypes and increased programmed cell death protein 1 (PD-1)+CD8+ T cells in the TME. Last, Trem2 deficiency enhanced the effectiveness of anti-PD-1 treatment, which may represent a therapeutic strategy for patients with GBM.
    DOI:  https://doi.org/10.1126/sciadv.ade3559
  14. Neuro Oncol. 2023 May 06. pii: noad087. [Epub ahead of print]
    Intracranial injection of NK cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma.
    Michael C Burger, Marie-Therese Forster, Annette Romanski, Florian Straßheimer, Jadranka Macas, Pia S Zeiner, Eike Steidl, Stefanie Herkt, Katharina J Weber, Jonathan Schupp, Jennifer H Lun, Maja I Strecker, Karolin Wlotzka, Pinar Cakmak, Corinna Opitz, Rosemol George, Iris C Mildenberger, Paulina Nowakowska, Congcong Zhang, Jasmin Röder, Elvira Müller, Kristina Ihrig, Karl-Josef Langen, Michael A Rieger, Eva Herrmann, Halvard Bönig, Patrick N Harter, Yvonne Reiss, Elke Hattingen, Franz Rödel, Karl H Plate, Torsten Tonn, Christian Senft, Joachim P Steinbach, Winfried S Wels.
      BACKGROUND: Glioblastoma (GB) is incurable at present without established treatment options for recurrent disease. In this phase I first-in-human clinical trial we investigated safety and feasibility of adoptive transfer of clonal CAR-NK cells (NK-92/5.28.z) targeting HER2, which is expressed at elevated levels by a subset of glioblastomas.METHODS: Nine patients with recurrent HER2-positive GB were treated with single doses of 1 x 10 7, 3 x 10 7 or 1 x 10 8 irradiated CAR-NK cells injected into the margins of the surgical cavity during relapse surgery. Imaging at baseline and follow-up, peripheral blood lymphocyte phenotyping and analyses of the immune architecture by multiplex immunohistochemistry and spatial digital profiling were performed.
    RESULTS: There were no dose-limiting toxicities, and none of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Five patients showed stable disease after relapse surgery and CAR-NK injection that lasted 7 to 37 weeks. Four patients had progressive disease. Pseudoprogression was found at injection sites in two patients, suggestive of a treatment-induced immune response. For all patients, median progression-free survival was 7 weeks, and median overall survival was 31 weeks. Furthermore, the level of CD8 + T-cell infiltration in recurrent tumor tissue prior to CAR-NK cell injection positively correlated with time to progression.
    CONCLUSIONS: Intracranial injection of HER2-targeted CAR-NK cells is feasible and safe in patients with recurrent GB. 1 x 10 8 NK-92/5.28.z cells was determined as the maximum feasible dose for a subsequent expansion cohort with repetitive local injections of CAR-NK cells.
    Keywords:  CAR-NK cells; HER2; adoptive immunotherapy; glioblastoma; phase I first-in-human clinical trial
    DOI:  https://doi.org/10.1093/neuonc/noad087
  15. Acta Neuropathol Commun. 2023 May 08. 11(1): 75
    TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma.
    Ayse N Menevse, Laura-Marie Ammer, Arabel Vollmann-Zwerenz, Marcell Kupczyk, Julia Lorenz, Lorraine Weidner, Abir Hussein, Julian Sax, Jasmin Mühlbauer, Nicole Heuschneider, Celine Rohrmus, Laura S Mai, Birgit Jachnik, Slava Stamova, Valentina Volpin, Franziska C Durst, Antonio Sorrentino, Maria Xydia, Vladimir M Milenkovic, Stefanie Bader, Frank K Braun, Christian Wetzel, Nathalie L Albert, Joerg-Christian Tonn, Peter Bartenstein, Martin Proescholdt, Nils O Schmidt, Ralf A Linker, Markus J Riemenschneider, Philipp Beckhove, Peter Hau.
      Glioblastoma (GB) IDH-wildtype is the most malignant primary brain tumor. It is particularly resistant to current immunotherapies. Translocator protein 18 kDa (TSPO) is upregulated in GB and correlates with malignancy and poor prognosis, but also with increased immune infiltration. Here, we studied the role of TSPO in the regulation of immune resistance of human GB cells. The role of TSPO in tumor immune resistance was experimentally determined in primary brain tumor initiating cells (BTICs) and cell lines through genetic manipulation of TSPO expression and subsequent cocultures with antigen specific cytotoxic T cells and autologous tumor-infiltrating T cells. Death inducing intrinsic and extrinsic apoptotic pathways affected by TSPO were investigated. TSPO-regulated genes mediating apoptosis resistance in BTICs were identified through gene expression analysis and subsequent functional analyses. TSPO transcription in primary GB cells correlated with CD8+ T cell infiltration, cytotoxic activity of T cell infiltrate, expression of TNFR and IFNGR and with the activity of their downstream signalling pathways, as well as with the expression of TRAIL receptors. Coculture of BTICs with tumor reactive cytotoxic T cells or with T cell-derived factors induced TSPO up-regulation through T cell derived TNFα and IFNγ. Silencing of TSPO sensitized BTICs against T cell-mediated cytotoxicity. TSPO selectively protected BTICs against TRAIL-induced apoptosis by regulating apoptosis pathways. TSPO also regulated the expression of multiple genes associated with resistance against apoptosis. We conclude that TSPO expression in GB is induced through T cell-derived cytokines TNFα and IFNγ and that TSPO expression protects GB cells against cytotoxic T cell attack through TRAIL. Our data thereby provide an indication that therapeutic targeting of TSPO may be a suitable approach to sensitize GB to immune cell-mediated cytotoxicity by circumventing tumor intrinsic TRAIL resistance.
    Keywords:  Anti-tumor immunity; GB; Immune-resistance; TRAIL-resistance; TSPO
    DOI:  https://doi.org/10.1186/s40478-023-01550-9
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