Global immune fingerprinting in glioblastoma patient peripheral blood reveals immune-suppression signatures associated with prognosis

Alban, Tyler J.; Alvarado, Alvaro G.; Sørensen, Mads D.; Bayik, Defne; Volovetz, Josephine; Serbinowski, Emily; Mulkearns-Hubert, Erin E.; Sinyuk, Maksim; Hale, James S.; Onzi, Giovana R.; McGraw, Mary; Huang, Pengjing; Grabowski, Matthew M.; Wathen, Connor; Ahluwalia, Manmeet; Radivoyevitch, Tomas; Kornblum, Harley I.; Kristensen, Bjarne Winther; Vogelbaum, Michael A.; Lathia, Justin D.

doi:10.1172/jci.insight.122264

Cited by 161 publications

(185 citation statements)

References 71 publications

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“…These patients were the same as those previously analyzed and reported by our group 13 . To analyze changes in the tumor microenvironment that occur in response to the 7-day pre-operative capecitabine treatment, three newly diagnosed GBM tumor samples and one recurrent GBM tumor sample were obtained via the Cleveland Clinic Brain Tumor Tissue Bank.…”

Section: Clinical Study Designmentioning

confidence: 64%

“…Peripheral blood MDSC concentrations were evaluated via flow cytometry (Supplemental Figure 1A) before treatment, during surgical resection and post-surgical resection on a per-patient basis to visualize trends in MDSC changes over time 13 (Figure 3A). Patients in the 300 mg bid and 450 mg bid capecitabine treatment arms had a reduction in MDSCs post-surgery, which was not observed in the 150 mg bid arm ( Figure 3A).…”

Section: Daily Oral Capecitabine Reduced the Expected Increase In Mdsmentioning

confidence: 99%

“…Of note, patient 3 in the 450 mg bid capecitabine treatment cohort (the only patient who did not have a reduction in peripheral MDSCs post-surgery) was noted to have multifocal GBM at the time of recurrence and enrollment in the trial. The distal site of recurrence was not resected, and the patient progressed To further determine the changes in tumor immune profiles associated with systemic capecitabine treatment, we analyzed GBM tissue from patients treated with capecitabine 5-7 days before surgery via CyTOF, which we previously used to identify immune shifts associated with GBM patient prognosis 13 . This immune panel consisted of 28 key cell surface immune system markers (Supplemental Figure 2A).…”

Section: Daily Oral Capecitabine Reduced the Expected Increase In Mdsmentioning

confidence: 99%

“…In multiple solid tumor models and clinical trials, elevated peripheral MDSC levels have been correlated with a more immunosuppressive phenotype, as well as with tumors that were refractory to immuneactivating therapies, including immune checkpoint inhibitors 26,27 . We previously observed that GBM patients with a better prognosis had reduced MDSCs in their tumors as well as in their peripheral circulation 13,22 . Previous studies have demonstrated that MDSCs in multiple tumor types can be reduced via low-dose chemotherapies [28][29][30] .…”

Section: Introductionmentioning

confidence: 98%

“…Multiple other cancers have faced similar obstacles to effective treatment, but this has been recently overcome with the use of immune-modulating therapies, and as a consequence, there is interest in trying to modify the immune system in GBM. Several immunomodulatory approaches are currently under clinical evaluation, including the use of immune checkpoint inhibitors, oncolytic viruses, dendritic cell vaccines, and CAR-T cell approaches 10 , but the wellappreciated immunosuppressive nature of GBM has proven difficult to overcome [11][12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

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Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells

Peereboom

Alban

Grabowski

et al. 2019

Preprint

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Background: Myeloid-derived suppressor cells (MDSCs) are elevated in glioblastoma (GBM) patient circulation, present in tumor tissue, and associated with poor prognosis. While low-dose chemotherapy reduces MDSCs in preclinical models, the use of this strategy to reduce MDSCs in GBM patients has yet to be evaluated. Methods:A phase 0/1 dose-escalation clinical trial was conducted in recurrent glioblastoma patients treated 5-7 days prior to surgery with low-dose chemotherapy via capecitabine followed by concomitant low-dose capecitabine and bevacizumab. Clinical outcomes, including progression-free and overall survival, were measured, along with safety and toxicity profiles. Over the treatment time course, circulating MDSC levels were measured by multi-parameter flow cytometry, and tumor tissue immune profiles were assessed via mass cytometry time-of-flight.Results: A total of 11 patients were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid, with a progression-free survival of 5.8 months (range of 1.8-27.8 months) and an overall survival of 11.5 months (range of 3->28.0 months) from trial enrollment. No serious adverse events related to the drug combination were observed. Compared to pre-treatment baseline, circulating MDSCs were found to be higher after surgery in the 150 mg treatment arm and lower in the 300 mg and 450 mg treatment arms. Increased cytotoxic immune infiltration was observed after low-dose capecitabine compared to untreated GBM patients in the 300 mg and 450 mg treatment arms. Conclusions:Low-dose, metronomic capecitabine in combination with bevacizumab is well tolerated in GBM patients and was associated with a reduction in circulating MDSC levels and an increase in cytotoxic immune infiltration into the tumor microenvironment.

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Section: Clinical Study Designmentioning

confidence: 64%

Section: Daily Oral Capecitabine Reduced the Expected Increase In Mdsmentioning

confidence: 99%

Section: Daily Oral Capecitabine Reduced the Expected Increase In Mdsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells

Peereboom

Alban

Grabowski

et al. 2019

Preprint

Self Cite

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Elucidating tumour‐associated microglia/macrophage diversity along glioblastoma progression and underACOD1deficiency

et al. 2022

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In glioblastoma (GBM), tumour-associated microglia/macrophages (TAMs) represent the major cell type of the stromal compartment and contribute to tumour immune escape mechanisms. Thus, targeting TAMs is emerging as a promising strategy for immunotherapy. However, TAM heterogeneity and metabolic adaptation along GBM progression represent critical features for the design of effective TAM-targeted therapies. Here, we comprehensively study the cellular and molecular changes of TAMs in the GL261 GBM mouse model, combining single-cell RNA-sequencing with flow cytometry and immunohistological analyses along GBM progression and in the absence of Acod1 (also known as Irg1), a key gene involved in the metabolic reprogramming of macrophages towards an anti-inflammatory phenotype. Similarly to patients, we identify distinct TAM profiles, mainly based on their ontogeny, that reiterate the idea that microglia-and macrophage-like cells show key transcriptional differences and dynamically adapt along GBM stages. Notably, we uncover decreased antigen-presenting cell features and immune reactivity in TAMs along tumour progression that are instead enhanced in Acod1-deficient mice. Overall, our results provide insight into TAM heterogeneity and highlight a novel role for Acod1 in TAM adaptation during GBM progression.

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Glycomaterials to Investigate the Functional Role of Aberrant Glycosylation in Glioblastoma

Tondepu

Karumbaiah

2021

Adv Healthcare Materials

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Glioblastoma (GBM) is a stage IV astrocytoma that carries a dismal survival rate of ≈10 months postdiagnosis and treatment. The highly invasive capacity of GBM and its ability to escape therapeutic challenges are key factors contributing to the poor overall survival rate. While current treatments aim to target the cancer cell itself, they fail to consider the significant role that the GBM tumor microenvironment (TME) plays in promoting tumor progression and therapeutic resistance. The GBM tumor glycocalyx and glycan-rich extracellular matrix (ECM), which are important constituents of the TME have received little attention as therapeutic targets. A wide array of aberrantly modified glycans in the GBM TME mediate tumor growth, invasion, therapeutic resistance, and immunosuppression. Here, an overview of the landscape of aberrant glycan modifications in GBM is provided, and the design and utility of 3D glycomaterials are discussed as a tool to evaluate glycan-mediated GBM progression and therapeutic efficacy. The development of alternative strategies to target glycans in the TME can potentially unveil broader mechanisms of restricting tumor growth and enhancing the efficacy of tumor-targeting therapeutics.

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Global immune fingerprinting in glioblastoma patient peripheral blood reveals immune-suppression signatures associated with prognosis

Cited by 161 publications

References 71 publications

Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells

Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells

Elucidating tumour‐associated microglia/macrophage diversity along glioblastoma progression and underACOD1deficiency

Glycomaterials to Investigate the Functional Role of Aberrant Glycosylation in Glioblastoma

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