bims-malgli 2023-04-16 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2023–04–16
eight papers selected by
Oltea Sampetrean, Keio University

Distinct Myeloid Derived Suppressor Cell Populations Promote Tumor Aggression in Glioblastoma.
The Glioma Immune Landscape: A Double-Edged Sword for Treatment Regimens.
TCF12 Deficiency Impairs the Proliferation of Glioblastoma Tumor Cells and Improves Survival.
Tumor progression is independent of tumor-associated macrophages in cell lineage-based mouse models of glioblastoma.
Proinflammatory macrophage activation by the polysialic acid-Siglec-16 axis is linked to increased survival of glioblastoma patients.
Proton boron capture therapy (PBCT) induces cell death and mitophagy in a heterotopic glioblastoma model.
Neuro-Oncology in Women: Clinical Considerations.
Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer.

bioRxiv. 2023 Mar 27. pii: 2023.03.26.534192. [Epub ahead of print]

Distinct Myeloid Derived Suppressor Cell Populations Promote Tumor Aggression in Glioblastoma.

Christina Jackson, Christopher Cherry, Sadhana Bom, Arbor G Dykema, Elizabeth Thompson, Ming Zheng, Zhicheng Ji, Wenpin Hou, Runzhe Li, Hao Zhang, John Choi, Fausto Rodriguez, Jon Weingart, Srinivasan Yegnasubramanian, Michael Lim, Chetan Bettegowda, Jonathan Powell, Jennifer Eliesseff, Hongkai Ji, Drew Pardoll.

The diversity of genetic programs and cellular plasticity of glioma-associated myeloid cells, and thus their contribution to tumor growth and immune evasion, is poorly understood. We performed single cell RNA-sequencing of immune and tumor cells from 33 glioma patients of varying tumor grades. We identified two populations characteristic of myeloid derived suppressor cells (MDSC), unique to glioblastoma (GBM) and absent in grades II and III tumors: i) an early progenitor population (E-MDSC) characterized by strong upregulation of multiple catabolic, anabolic, oxidative stress, and hypoxia pathways typically observed within tumor cells themselves, and ii) a monocytic MDSC (M-MDSC) population. The E-MDSCs geographically co-localize with a subset of highly metabolic glioma stem-like tumor cells with a mesenchymal program in the pseudopalisading region, a pathognomonic feature of GBMs associated with poor prognosis. Ligand-receptor interaction analysis revealed symbiotic cross-talk between the stemlike tumor cells and E-MDSCs in GBM, whereby glioma stem cells produce chemokines attracting E-MDSCs, which in turn produce growth and survival factors for the tumor cells. Our large-scale single-cell analysis elucidated unique MDSC populations as key facilitators of GBM progression and mediators of tumor immunosuppression, suggesting that targeting these specific myeloid compartments, including their metabolic programs, may be a promising therapeutic intervention in this deadly cancer.
One-Sentence Summary: Aggressive glioblastoma harbors two unique myeloid populations capable of promoting stem-like properties of tumor cells and suppressing T cell function in the tumor microenvironment.

DOI: https://doi.org/10.1101/2023.03.26.534192
Cancers (Basel). 2023 Mar 28. pii: 2024. [Epub ahead of print]15(7):

The Glioma Immune Landscape: A Double-Edged Sword for Treatment Regimens.

Sukrit Mahajan, Mirko H H Schmidt, Ulrike Schumann.

  Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that involves enhancing the immune response to fight the battle against cancer more effectively. While it has shown success against different cancer types, immunotherapy faces major roadblocks in glioma treatment. These involve the blood brain barrier, tumor heterogeneity and an immunosuppressive glioma microenvironment, among other factors. Additionally, the interaction of the peripheral immune system with the central nervous system provides another challenge for immunotherapeutic regimens. For modulating different immune cell populations to counter glioma cells, it is important to expand our knowledge about their role within the glioma microenvironment; therefore, herein, we review the different immune cell populations found in the glioma microenvironment and navigate through the various shortcomings of current immunotherapies for glioma. We conclude by providing an insight into ongoing pre-clinical and clinical trials for glioma therapies.

Keywords:  clinical trials; glioblastoma therapy; glioma; immune landscape; immunotherapy

DOI:  https://doi.org/10.3390/cancers15072024
Cancers (Basel). 2023 Mar 29. pii: 2033. [Epub ahead of print]15(7):

TCF12 Deficiency Impairs the Proliferation of Glioblastoma Tumor Cells and Improves Survival.

Yunong Pang, Sichang Zhou, Paul Zumbo, Doron Betel, Babacar Cisse.

  Isocitrate dehydrogenase (IDH)-wild-type glioblastoma (GBM) is the most common and aggressive primary brain tumor which carries a very poor overall prognosis and is universally fatal. Understanding the transcriptional regulation of the proliferation of GBM tumor cells is critical for developing novel and effective treatments. In this study, we investigate the role of the transcription factor TCF12 in the regulation of GBM proliferation using human and murine GBM cell lines and an in vivo GBM xenograft model. Our study shows that TCF12 deficiency severely impairs proliferation of tumor cells in vitro by disrupting/blocking the G1 to S phase transition. We also discover that TCF12 loss significantly improves animal survival and that TCF12-deficient tumors grow much slower in vivo. Overexpression of TCF12, on the other hand, leads to an increase in the proliferation of tumor cells in vitro and more aggressive tumor progression in vivo. Interestingly, loss of TCF12 leads to upregulation of signature genes of the oligodendrocytic lineage in GBM stem cells, suggesting a role for TCF12 in inhibiting differentiation along the oligodendrocytic lineage. Transcriptomic data also reveals that loss of TCF12 leads to dysregulation of the expression of key genes in the cell cycle. Our work demonstrates critical roles of TCF12 in GBM tumor progression.

Keywords:  TCF12; cell cycle and proliferation; glioblastomas (GBMs); oligodendrocytic lineage; xenograft

DOI:  https://doi.org/10.3390/cancers15072033
Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2222084120

Tumor progression is independent of tumor-associated macrophages in cell lineage-based mouse models of glioblastoma.

Mollie E Chipman, Zilai Wang, Daochun Sun, Alicia M Pedraza, Tejus A Bale, Luis F Parada.

  Macrophage targeting therapies have had limited clinical success in glioblastoma (GBM). Further understanding the GBM immune microenvironment is critical for refining immunotherapeutic approaches. Here, we use genetically engineered mouse models and orthotopic transplantation-based GBM models with identical driver mutations and unique cells of origin to examine the role of tumor cell lineage in shaping the immune microenvironment and response to tumor-associated macrophage (TAM) depletion therapy. We show that oligodendrocyte progenitor cell lineage-associated GBMs (Type 2) recruit more immune infiltrates and specifically monocyte-derived macrophages than subventricular zone neural stem cell-associated GBMs (Type 1). We then devise a TAM depletion system that offers a uniquely robust and sustained TAM depletion. We find that extensive TAM depletion in these cell lineage-based GBM models affords no survival benefit. Despite the lack of survival benefit of TAM depletion, we show that Type 1 and Type 2 GBMs have unique molecular responses to TAM depletion. In sum, we demonstrate that GBM cell lineage influences TAM ontogeny and abundance and molecular response to TAM depletion.

Keywords:  CSF1R inhibition; cell of origin; glioblastoma; microglia; tumor-associated macrophages

DOI:  https://doi.org/10.1073/pnas.2222084120
Clin Cancer Res. 2023 Apr 14. pii: CCR-22-1488. [Epub ahead of print]

Proinflammatory macrophage activation by the polysialic acid-Siglec-16 axis is linked to increased survival of glioblastoma patients.

Hauke Thiesler, Lina Gretenkort, Leonie Hoffmeister, Iris Albers, Luisa Ohlmeier, Iris Röckle, Andrea Verhagen, Rouzbeh Banan, Nora Köpcke, Nicole Krönke, Friedrich Feuerhake, Felix Behling, Alonso Barrantes-Freer, Dorothee Mielke, Veit Rohde, Bujung Hong, Ajit Varki, Kerstin Schwabe, Joachim K Krauss, Christine Stadelmann, Christian Hartmann, Herbert Hildebrandt.

PURPOSE: Interactions with tumor-associated microglia and macrophages (TAM) are critical for glioblastoma progression. Polysialic acid (polySia) is a tumor-associated glycan, but its frequency of occurrence and its prognostic value in glioblastoma are disputed. Through interactions with the opposing immune receptors Siglec-11 and Siglec-16, polySia is implicated in the regulation of microglia and macrophage activity. However, due to a nonfunctional SIGLEC16P allele, SIGLEC16 penetrance is less than 40%. Here, we explored possible consequences of SIGLEC16 status and tumor cell-associated polySia on glioblastoma outcome.
EXPERIMENTAL DESIGN: FFPE specimens of two independent cohorts with 70 and 100 newly diagnosed glioblastoma patients were retrospectively analyzed for SIGLEC16 and polySia status in relation to overall survival. Inflammatory TAM activation was assessed in tumors, in heterotypic tumor spheroids consisting of polySia-positive glioblastoma cells and Siglec-16-positive or -negative macrophages, and by exposing Siglec-16-positive or -negative macrophages to glioblastoma cell-derived membrane fractions.
RESULTS: Overall survival of SIGLEC16 carriers with polySia-positive tumors was increased. Consistent with proinflammatory Siglec-16 signaling, levels of TAM positive for the M2 marker CD163 were reduced, whereas the M1 marker CD74 and TNF expression were increased, and CD8+ T cells enhanced in SIGLEC16 polySia double-positive tumors. Correspondingly, TNF production was elevated in heterotypic spheroid cultures with Siglec-16-expressing macrophages. Furthermore, a higher, mainly M1-like cytokine release and activating immune signaling was observed in SIGLEC16-positive as compared to SIGLEC16-negative macrophages confronted with glioblastoma cell-derived membranes.
CONCLUSIONS: Collectively, these results strongly suggest that proinflammatory TAM activation causes the better outcome in glioblastoma patients with a functional polySia-Siglec-16 axis.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-1488
Commun Biol. 2023 04 08. 6(1): 388

Proton boron capture therapy (PBCT) induces cell death and mitophagy in a heterotopic glioblastoma model.

Francesco Paolo Cammarata, Filippo Torrisi, Nunzio Vicario, Valentina Bravatà, Alessandro Stefano, Lucia Salvatorelli, Simona D'Aprile, Pierangela Giustetto, Giusi Irma Forte, Luigi Minafra, Marco Calvaruso, Selene Richiusa, Giuseppe Antonio Pablo Cirrone, Giada Petringa, Giuseppe Broggi, Sebastiano Cosentino, Fabrizio Scopelliti, Gaetano Magro, Danilo Porro, Massimo Libra, Massimo Ippolito, Giorgio Russo, Rosalba Parenti, Giacomo Cuttone.

Despite aggressive therapeutic regimens, glioblastoma (GBM) represents a deadly brain tumor with significant aggressiveness, radioresistance and chemoresistance, leading to dismal prognosis. Hypoxic microenvironment, which characterizes GBM, is associated with reduced therapeutic effectiveness. Moreover, current irradiation approaches are limited by uncertain tumor delineation and severe side effects that comprehensively lead to unsuccessful treatment and to a worsening of the quality of life of GBM patients. Proton beam offers the opportunity of reduced side effects and a depth-dose profile, which, unfortunately, are coupled with low relative biological effectiveness (RBE). The use of radiosensitizing agents, such as boron-containing molecules, enhances proton RBE and increases the effectiveness on proton beam-hit targets. We report a first preclinical evaluation of proton boron capture therapy (PBCT) in a preclinical model of GBM analyzed via μ-positron emission tomography/computed tomography (μPET-CT) assisted live imaging, finding a significant increased therapeutic effectiveness of PBCT versus proton coupled with an increased cell death and mitophagy. Our work supports PBCT and radiosensitizing agents as a scalable strategy to treat GBM exploiting ballistic advances of proton beam and increasing therapeutic effectiveness and quality of life in GBM patients.

DOI: https://doi.org/10.1038/s42003-023-04770-w
Neurol Clin. 2023 05;pii: S0733-8619(22)00091-3. [Epub ahead of print]41(2): 331-342

Neuro-Oncology in Women: Clinical Considerations.

Lauren Singer, Ditte Primdahl, Priya Kumthekar.

  Sex differences play a large role in oncology. It has long been discussed that the incidence of different types of tumors varies by sex, and this holds in neuro-oncology. There are also profound survival sex differences, biologic factors, and treatment effects. This review aims to summarize some of the main sex differences observed in primary brain tumors and goes on to focus specifically on gliomas and meningiomas, as these are two commonly encountered primary brain tumors in clinical practice. Additionally, considerations unique to female individuals, including pregnancy and breastfeeding, are explored. This review sheds light on many of the unique attributes that must be considered when diagnosing and treating female patients with primary brain tumors in clinical practice.

Keywords:  Glioma; Meningioma; Oncology

DOI:  https://doi.org/10.1016/j.ncl.2022.10.005
Sci Transl Med. 2023 Apr 12. 15(691): eadd1016

Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer.

Stefan Naulaerts, Angeliki Datsi, Daniel M Borras, Asier Antoranz Martinez, Julie Messiaen, Isaure Vanmeerbeek, Jenny Sprooten, Raquel S Laureano, Jannes Govaerts, Dena Panovska, Marleen Derweduwe, Michael C Sabel, Marion Rapp, Weiming Ni, Sean Mackay, Yannick Van Herck, Lendert Gelens, Tom Venken, Sanket More, Oliver Bechter, Gabriele Bergers, Adrian Liston, Steven De Vleeschouwer, Benoit J Van Den Eynde, Diether Lambrechts, Michiel Verfaillie, Francesca Bosisio, Sabine Tejpar, Jannie Borst, Rüdiger V Sorg, Frederik De Smet, Abhishek D Garg.

Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8+ T cells remain disputed. Using multiomics analysis of CD8+ T cell features across multiple patient cohorts and tumor types, we identified tumor niche-dependent exhausted and other types of hypofunctional CD8+ T cell states. CD8+ T cells in "supportive" niches, like melanoma or lung cancer, exhibited features of tumor reactivity-driven exhaustion (CD8+ TEX). These included a proficient effector memory phenotype, an expanded T cell receptor (TCR) repertoire linked to effector exhaustion signaling, and a cancer-relevant T cell-activating immunopeptidome composed of largely shared cancer antigens or neoantigens. In contrast, "nonsupportive" niches, like glioblastoma, were enriched for features of hypofunctionality distinct from canonical exhaustion. This included immature or insufficiently activated T cell states, high wound healing signatures, nonexpanded TCR repertoires linked to anti-inflammatory signaling, high T cell-recognizable self-epitopes, and an antiproliferative state linked to stress or prodeath responses. In situ spatial mapping of glioblastoma highlighted the prevalence of dysfunctional CD4+:CD8+ T cell interactions, whereas ex vivo single-cell secretome mapping of glioblastoma CD8+ T cells confirmed negligible effector functionality and a promyeloid, wound healing-like chemokine profile. Within immuno-oncology clinical trials, anti-programmed cell death protein 1 (PD-1) immunotherapy facilitated glioblastoma's tolerogenic disparities, whereas dendritic cell (DC) vaccines partly corrected them. Accordingly, recipients of a DC vaccine for glioblastoma had high effector memory CD8+ T cells and evidence of antigen-specific immunity. Collectively, we provide an atlas for assessing different CD8+ T cell hypofunctional states in immunogenic versus nonimmunogenic cancers.

DOI: https://doi.org/10.1126/scitranslmed.add1016