Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma
Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2017-04-01
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| Series: | OncoImmunology |
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| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1295903 |
| _version_ | 1811204294281527296 |
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| author | Abhishek D. Garg Lien Vandenberk Matthias Van Woensel Jochen Belmans Marco Schaaf Louis Boon Steven De Vleeschouwer Patrizia Agostinis |
| author_facet | Abhishek D. Garg Lien Vandenberk Matthias Van Woensel Jochen Belmans Marco Schaaf Louis Boon Steven De Vleeschouwer Patrizia Agostinis |
| author_sort | Abhishek D. Garg |
| collection | DOAJ |
| description | Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also “guide and prioritize” preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression. Based on these analyses, we found that predictive biomarkers of ICI responsiveness exhibited inconsistent patterns in GBM patients, i.e., they either predicted ICI resistance (as compared with typical ICI-responsive cancer-types like melanoma, lung cancer or bladder cancer) or susceptibility to therapeutic targeting of CTLA4 or IDO1. On the other hand, our comprehensive literature meta-analysis and preclinical testing of ICIs using an orthotopic GL261-glioma mice model, indicated significant antitumor properties of anti-PD1 antibody, whereas blockade of IDO1 or CTLA4 either failed or provided very marginal advantage. These trends raise the need to better assess the applicability of ICIs and associated biomarkers for GBM. |
| first_indexed | 2024-04-12T03:10:37Z |
| format | Article |
| id | doaj.art-3a0cee7e7812429bb36bd26111abdbdf |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-04-12T03:10:37Z |
| publishDate | 2017-04-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-3a0cee7e7812429bb36bd26111abdbdf2022-12-22T03:50:21ZengTaylor & Francis GroupOncoImmunology2162-402X2017-04-016410.1080/2162402X.2017.12959031295903Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastomaAbhishek D. Garg0Lien Vandenberk1Matthias Van Woensel2Jochen Belmans3Marco Schaaf4Louis Boon5Steven De Vleeschouwer6Patrizia Agostinis7KU Leuven University of LeuvenKU Leuven University of LeuvenResearch Group – Experimental Neurosurgery & Neuroanatomy, KU Leuven University of LeuvenKU Leuven University of LeuvenKU Leuven University of LeuvenBioceros BVResearch Group – Experimental Neurosurgery & Neuroanatomy, KU Leuven University of LeuvenKU Leuven University of LeuvenGlioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also “guide and prioritize” preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression. Based on these analyses, we found that predictive biomarkers of ICI responsiveness exhibited inconsistent patterns in GBM patients, i.e., they either predicted ICI resistance (as compared with typical ICI-responsive cancer-types like melanoma, lung cancer or bladder cancer) or susceptibility to therapeutic targeting of CTLA4 or IDO1. On the other hand, our comprehensive literature meta-analysis and preclinical testing of ICIs using an orthotopic GL261-glioma mice model, indicated significant antitumor properties of anti-PD1 antibody, whereas blockade of IDO1 or CTLA4 either failed or provided very marginal advantage. These trends raise the need to better assess the applicability of ICIs and associated biomarkers for GBM.http://dx.doi.org/10.1080/2162402X.2017.1295903cancer immunotherapycopy-number alterations (cna)ctla4high-grade gliomaido1immune-checkpoint blockers (icbs)mutational burdenneoantigenpatient prognosispd1t cellstreg cells |
| spellingShingle | Abhishek D. Garg Lien Vandenberk Matthias Van Woensel Jochen Belmans Marco Schaaf Louis Boon Steven De Vleeschouwer Patrizia Agostinis Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma OncoImmunology cancer immunotherapy copy-number alterations (cna) ctla4 high-grade glioma ido1 immune-checkpoint blockers (icbs) mutational burden neoantigen patient prognosis pd1 t cells treg cells |
| title | Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma |
| title_full | Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma |
| title_fullStr | Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma |
| title_full_unstemmed | Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma |
| title_short | Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma |
| title_sort | preclinical efficacy of immune checkpoint monotherapy does not recapitulate corresponding biomarkers based clinical predictions in glioblastoma |
| topic | cancer immunotherapy copy-number alterations (cna) ctla4 high-grade glioma ido1 immune-checkpoint blockers (icbs) mutational burden neoantigen patient prognosis pd1 t cells treg cells |
| url | http://dx.doi.org/10.1080/2162402X.2017.1295903 |
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