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NMR Biomed. 2020 Jan 11:e4229. doi: 10.1002/nbm.4229. [Epub ahead of print]

Anti-tumour immune response in GL261 glioblastoma generated by Temozolomide Immune-Enhancing Metronomic Schedule monitored with MRSI-based nosological images.

Author information

1
Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici Cs, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
2
Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 08193 Cerdanyola del Vallés, Spain.
3
Unit of Murine and Comparative Pathology, Department of Animal Medicine and Animal Surgery, Veterinary Faculty, UAB, Cerdanyola del Vallès, Spain.
4
Department of Applied Mathematics, Liverpool John Moores University, Liverpool, UK.
5
Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Abstract

Glioblastomas (GB) are brain tumours with poor prognosis even after aggressive therapy. Improvements in both therapeutic and follow-up strategies are urgently needed. In previous work we described an oscillatory pattern of response to Temozolomide (TMZ) using a standard administration protocol, detected through MRSI-based machine learning approaches. In the present work, we have introduced the Immune-Enhancing Metronomic Schedule (IMS) with an every 6-d TMZ administration at 60 mg/kg and investigated the consistence of such oscillatory behaviour. A total of n = 17 GL261 GB tumour-bearing C57BL/6j mice were studied with MRI/MRSI every 2 d, and the oscillatory behaviour (6.2 ± 1.5 d period from the TMZ administration day) was confirmed during response. Furthermore, IMS-TMZ produced significant improvement in mice survival (22.5 ± 3.0 d for controls vs 135.8 ± 78.2 for TMZ-treated), outperforming standard TMZ treatment. Histopathological correlation was investigated in selected tumour samples (n = 6) analyzing control and responding fields. Significant differences were found for CD3+ cells (lymphocytes, 3.3 ± 2.5 vs 4.8 ± 2.9, respectively) and Iba-1 immunostained area (microglia/macrophages, 16.8% ± 9.7% and 21.9% ± 11.4%, respectively). Unexpectedly, during IMS-TMZ treatment, tumours from some mice (n = 6) fully regressed and remained undetectable without further treatment for 1 mo. These animals were considered "cured" and a GL261 re-challenge experiment performed, with no tumour reappearance in five out of six cases. Heterogeneous therapy response outcomes were detected in tumour-bearing mice, and a selected group was investigated (n = 3 non-responders, n = 6 relapsing tumours, n = 3 controls). PD-L1 content was found ca. 3-fold increased in the relapsing group when comparing with control and non-responding groups, suggesting that increased lymphocyte inhibition could be associated to IMS-TMZ failure. Overall, data suggest that host immune response has a relevant role in therapy response/escape in GL261 tumours under IMS-TMZ therapy. This is associated to changes in the metabolomics pattern, oscillating every 6 d, in agreement with immune cycle length, which is being sampled by MRSI-derived nosological images.

KEYWORDS:

PD-L1; glioma; immune memory, TMZ; immune response; metronomic therapy; orthotopic tumours

PMID:
31926117
DOI:
10.1002/nbm.4229

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