Anti-tumour immune response in GL261 glioblastoma generated by Temozolomide Immune-Enhancing Metronomic Schedule monitored with MRSI-based nosological images
Wu, Shuang (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Calero-Perez, Pilar (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Villamañán de Santiago, Lucía (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Arias-Ramos, Nuria (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pumarola i Batlle, Martí (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animals)
Ortega-Martorell, Sandra (Liverpool John Moores University. Department of Applied Mathematics)
Julià Sapé, Ma. Margarita (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Arús i Caraltó, Carles (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Candiota Silveira, Ana Paula (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Universitat Autònoma de Barcelona. SGR-Grup de Recerca d'Aplicacions Biomèdiques de l'Espectroscòpia de Ressonància Magnètica Nuclear de Catalunya

Data:	2020
Resum:	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.
Ajuts:	European Commission 777222 Ministerio de Sanidad y Consumo CB06/01/0010 Ministerio de Economía y Competitividad BES-2012-055741 Ministerio de Economía y Competitividad SAF2014-52332-R
Nota:	Altres ajuts: China Scholarship Council. Grant Number: 201606990027 ; Universitat Autònoma de Barcelona. Grant Numbers: 13ª Convocatoria PIF, 14ª Convocatoria PIF - 19612
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Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Matèria:	Glioma ; Immune memory ; TMZ ; Immune response ; Metronomic therapy ; Orthotopic tumours ; PD-L1
Publicat a:	NMR in biomedicine, Vol. 33 Núm. 4 (2020) , p. e4229, ISSN 1099-1492

DOI: 10.1002/nbm.4229
PMID: 31926117

Postprint 25 p, 1.1 MB

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