Levine and Nobre et al. developed a 103-gene immuno-oncology transcriptomic panel, including the validated 18-gene tumor inflammation signature (TIS), using the NanoString nCounter system to profile tumor immune microenvironments in 1382 pediatric brain tumors. In low-grade BRAF V600E-mutant gliomas, high TIS scores showed negative prognostic significance, supporting testing ICB in combination with BRAFi. High-grade gliomas showed immune activation, T cell infiltration, increased inflammation, and elevated expression of targetable immune checkpoints. High TIS scores predicted responses to immune checkpoint inhibition in high-grade MMRd gliomas.
Contributed by Shishir Pant
ABSTRACT: With the success of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important; however in pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay and used it to profile a diverse range of 1382 samples with detailed clinical and molecular annotation. In low-grade gliomas we identify distinct patterns of immune activation with prognostic significance in BRAF V600E-mutant tumors. In high-grade gliomas, we observe immune activation and T-cell infiltrates in tumors that have historically been considered immune cold, as well as genomic correlates of inflammation levels. In mismatch repair deficient high-grade gliomas, we find that high tumor inflammation signature is a significant predictor of response to immune checkpoint inhibition, and demonstrate the potential for multimodal biomarkers to improve treatment stratification. Importantly, while overall patterns of immune activation are observed for histologically and genetically defined tumor types, there is significant variability within each entity, indicating that the TIME must be evaluated as an independent feature from diagnosis. In sum, in addition to the histology and molecular profile, this work underscores the importance of reporting on the TIME as an essential axis of cancer diagnosis in the era of personalized medicine.
Author Info: (1) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Department of Laboratory Medicine and Pathobiology, University of Tor
Author Info: (1) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. Clinician Investigator Program, University of British Columbia, Vancouver, BC, Canada. (2) Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. Department of Paediatrics, University of Alberta, Edmonton, AB, Canada. (3) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Neuro-Oncology Unit, Division of Haematology Oncology, The Hospital for Sick Children, Toronto, ON, Canada. (4) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. (5) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. (6) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. (7) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. (8) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. (9) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. (10) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. (11) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. (12) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. (13) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. (14) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. (15) Clinic of Pediatric Oncology and Hematology, University Children's Hospital, Bansk Bystrica, Slovakia. (16) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Neuro-Oncology Unit, Division of Haematology Oncology, The Hospital for Sick Children, Toronto, ON, Canada. (17) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Neuro-Oncology Unit, Division of Haematology Oncology, The Hospital for Sick Children, Toronto, ON, Canada. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada. (18) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. (19) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. Neuro-Oncology Unit, Division of Haematology Oncology, The Hospital for Sick Children, Toronto, ON, Canada. (20) Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. cynthia.hawkins@sickkids.ca. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. cynthia.hawkins@sickkids.ca. Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. cynthia.hawkins@sickkids.ca.
