Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma

Lee, Juyeun; Nicosia, Michael; Hong, Ellen S.; Silver, Daniel J.; Li, Cathy; Bayik, Defne; Watson, Dionysios C.; Lauko, Adam; Kay, Kristen; Wang, Sabrina; Johnson, Sarah K.; McGraw, Mary; Grabowski, Matthew M.; Kish, Danielle D.; Desai, Amar; Goodman, Wendy A.; Cameron, Scott J.; Okada, Hideho; Valujskikh, Anna; Fairchild, Robert L.; Ahluwalia, Manmeet; Lathia, Justin D.

doi:10.1158/2159-8290.cd-22-0869

Cited by 31 publications

(19 citation statements)

References 48 publications

(52 reference statements)

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“…In complement, Li et al, found that ibrutinib reduced CD8 + T cell exhaustion both in the in vitro setting and in BTK deficient mice, specifically by downregulating inhibitory receptors and increasing cytokine production [ 51 ]. The presence of T cell inhibitory signaling has been implicated in assistance with disease progression in glioblastomas thus further studies are warranted to further delineate the influence of BTK/BMX inhibition on T-cell infiltration, microglial behaviors and cytokine production within immunocompetent models [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model

Lim,

Kwak,

Kang

et al. 2024

acta neuropathol commun

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In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently impair aortic endothelial adhesion and increase rodent glioma model survival in combination with cytotoxic therapy. Yet additional research is required to understand ibrutinib’s effect on BTB function. In this study, we detail baseline BTK expression in glioma cells and its surrounding vasculature, then measure endothelial junctional expression/function changes with varied ibrutinib doses in vitro. Rat glioma cells and rodent glioma models were treated with ibrutinib alone (1–10 µM and 25 mg/kg) and in combination with doxil (10–100 µM and 3 mg/kg) to assess additive effects on viability, drug concentrations, tumor volume, endothelial junctional expression and survival. We found that ibrutinib, in a dose-dependent manner, decreased brain endothelial cell–cell adhesion over 24 h, without affecting endothelial cell viability (p < 0.005). Expression of tight junction gene and protein expression was decreased maximally 4 h after administration, along with inhibition of efflux transporter, ABCB1, activity. We demonstrated an additive effect of ibrutinib with doxil on rat glioma cells, as seen by a significant reduction in cell viability (p < 0.001) and increased CNS doxil concentration in the brain (56 ng/mL doxil alone vs. 74.6 ng/mL combination, p < 0.05). Finally, Ibrutinib, combined with doxil, prolonged median survival in rodent glioma models (27 vs. 16 days, p < 0.0001) with brain imaging showing a − 53% versus − 75% volume change with doxil alone versus combination therapy (p < 0.05). These findings indicate ibrutinib’s ability to increase brain endothelial permeability via junctional disruption and efflux inhibition, to increase BTB drug entry and prolong rodent glioma model survival. Our results motivate the need to identify other BTB modifiers, all with the intent of improving survival and reducing systemic toxicities.

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Section: Discussionmentioning

confidence: 99%

Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model

Lim,

Kwak,

Kang

et al. 2024

acta neuropathol commun

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“…KDM6B deficiency inhibits secretion of immunosuppressive mediators such as MAF BZIP transcription factor B (MAFB), suppressor of cytokine signaling 3 (SOCS3), and signal regulatory protein alpha (SIRPA), thereby enhancing the efficacy of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy [ 52 ]. In humans, presence of X chromosome inactivation escape gene KDM6A [ 53 ] results in lower CD8 + T cell levels in male GBM microenvironments than in female GBM microenvironments [ 54 ]. Moreover, T cells in the male GBM microenvironment are more prone to exhaustion.…”

Section: The Immune Regulation In Glioblastomamentioning

confidence: 99%

“…Combination therapy involving DNA damage response inhibitors (DDRi) and RT in H3.3-G34R pHGG mice can significantly increase median survival [ 68 ]. Table 1 shows the epigenetic alterations associated with immune regulation in GBM [ 49 – 52 , 54 , 63 , 66 , 68 – 84 ].…”

Section: The Immune Regulation In Glioblastomamentioning

confidence: 99%

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Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives

Lin,

Liu,

et al. 2024

J Hematol Oncol

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Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4–8%) of CD45+ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.

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“…Tumor-intrinsic sex differences include differences in enhancer landscapes, glutamine metabolism, and oncogenic transformation 8,9 . Tumor-extrinsic factors contributing to sex bias include microglial activation and anti-tumor immunity 10,11 . However, the mechanisms underlying these sex-specific differences remain unknown.…”

Section: Introductionmentioning

confidence: 99%

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma

Hong,

Wang,

Ponti

et al. 2024

Preprint

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Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown. Methods: We leveraged previously published paired miRNA and mRNA sequencing of 39 GBM patients (22 male, 17 female) to identify sex-biased miRNAs. We further interrogated a separate single-cell RNA sequencing dataset of 110 GBM patients to examine whether differences in miRNA target gene expression were tumor cell intrinsic or tumor cell extrinsic. Results were validated in a panel of patient-derived cell models. Results: We identified 10 sex-biased miRNAs (adjusted < 0.1), of which 3 were more highly expressed in males and 7 more highly expressed in females. Of these, miR-644a was higher in females, and increased expression of miR-644a target genes was significantly associated with decreased overall survival (HR 1.3, p = 0.02). Furthermore, analysis of an independent single-cell RNA sequencing dataset confirmed sex-specific expression of miR-644a target genes in tumor cells (p < 10-15). Among patient derived models, miR-644a was expressed a median of 4.8-fold higher in females compared to males. Conclusions: Our findings implicate miR-644a as a candidate tumor cell-intrinsic regulator of sex-biased gene expression in GBM.

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Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma

Cited by 31 publications

References 48 publications

Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model

Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model

Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma

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