Molecular profiling of an osseous metastasis in glioblastoma during checkpoint inhibition: potential mechanisms of immune escape

Abstract

Peripheral metastases of glioblastoma (GBM) are very rare despite the ability of GBM cells to pass through the blood-brain barrier and be disseminated through the peripheral blood. Here, we describe a detailed genetic and immunological characterization of a GBM metastasis in the skeleton, which occurred during anti-PD-1 immune checkpoint therapy. We performed whole genome sequencing (WGS) and 850 K methylation profiling of the primary and recurrent intracranial GBM as well as one of the bone metastases. Copy number alterations (CNA) and mutational profiles were compared to known genomic alterations in the TCGA data base. In addition, immunophenotyping of the peripheral blood was performed. The patient who was primarily diagnosed with IDHwildtype GBM. After the resection of the first recurrence, progressive intracranial re-growth was again detected, and chemotherapy was replaced by PD-1 checkpoint inhibition, which led to a complete intracranial remission. Two months later MR-imaging revealed multiple osseous lesions. Biopsy confirmed the GBM origin of the skeleton metastases. Immunophenotyping reflected the effective activation of a peripheral T-cell response, with, however, increase of regulatory T cells during disease progression. WGS sequencing demonstrated distinct genomic alterations of the GBM metastasis, with gains along chromosomes 3 and 9 and losses along chromosome 4, 10, and 11. Mutational analysis showed mutations in potentially immunologically relevant regions. Additionally, we correlated tumour-infiltrating lymphocyte and microglia presence to the occurrence of circulating tumour cells (CTCs) in a larger cohort and found a decreased infiltration of cytotoxic T cells in patients positive for CTCs. This study exemplifies that the tumour microenvironment may dictate the response to immune checkpoint therapy. In addition, our study highlights the fact that despite an effective control of intracranial GBM, certain tumour clones have the ability to evade the tumour-specific T-cell response and cause progression even outside of the CNS.

Chlorogenic acid induces apoptosis, inhibits metastasis and improves antitumor immunity in breast cancer via the NF‑κB signaling pathway

“…In the pulmonary metastasis model of 4T1, treatment with CGA significantly decreased metastatic nodules in lung tissues. Tumor immune escape, which is featured as suppressive antitumor immunity, is responsible for tumor malignancy and distant metastasis ( 47 ). Based on the efficient anti-metastasis efficacy of CGA, the present study investigated the effect of CGA on antitumor immunity.…”

Bone Metastases of Glioblastoma: A Case Report and Review of the Literature

“…Although GBM cells can pass through the BBB and be disseminated throughout the peripheral blood ( 7 ), extracranial metastasis of GBM is rare, with a reported incidence of approximately 0.4% to 2% ( 6 , 18 , 19 ). This rare phenomenon is also attributed to the absence of lymphatics in the brain ( 20 ).…”

“…Later studies indicated a lymphatic pathway of GBM metastasis (30). Malte Mohme et al described that extracranial metastasis of GBM may also be related to genetic drivers and immune escape (7). GBM metastasizing to the distal limbs has not been reported.…”

“…Metastatic diffusion of cerebrospinal fluid (CSF) is observed in some cases. Peripheral metastases of GBM are very rare despite the ability of GBM cells to pass through the blood–brain barrier (BBB) and be disseminated throughout the peripheral blood ( 7 ). The mechanism of their diffusion is not well known.…”

Transcriptional Characteristics of IDH-Wild Type Glioma Subgroups Highlight the Biological Processes Underlying Heterogeneity of IDH-Wild Type WHO Grade IV Gliomas

“…Developing immunotherapy for gliomas has also attracted extensive investigation (Ogbomo et al, 2011;Topalian et al, 2015). Transcriptional characteristics can also reflect the status of tumor immune-microenvironment, which is critical for developing immunotherapy for IDH-wild type gliomas (Zhang et al, 2017;Cai et al, 2018;Martinez-Lage et al, 2019;Mohme et al, 2020;Zha et al, 2020). Here, we observed a positive correlation between signature risk scores and the number of immune-infiltrating cells in IDH-wild type WHO grade IV gliomas.…”