Oncoimmunology. 2018 Sep 5;8(1):e1512943. doi: 10.1080/2162402X.2018.1512943. eCollection 2019.
Identification of PD-L2, B7-H3 and CTLA-4 immune checkpoint proteins in genetic subtypes of meningioma.
Proctor DT1,2,3, Patel Z1,2,3, Lama S1,2,3, Resch L4, van Marle G5, Sutherland GR1,2,3.
1
Project neuroArm, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
2
Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
3
Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada.
4
Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
5
Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Meningioma is the most common brain tumor in adults. Surgical resection remains the primary treatment. No chemotherapy exists. However, gene mutations now could explain ~ 80% of meningioma and targeted therapies based on these are being investigated. Furthermore, with the recent discovery of PD-L1 in malignant meningioma, clinical trials using immunotherapy have commenced. Here, we report for the first time the expression profiles of immune checkpoint proteins PD-L2, B7-H3 and CTLA-4 in meningioma and their association to common gene mutations. PD-L2 and B7-H3 expression was significantly greater than all immune checkpoint proteins studied, and particularly elevated in patients with gene mutations affecting the PI3K/AKT/mTOR pathway. CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring a PIK3CA or SMO mutation. These results identify novel targets for immunotherapy irrespective of grade and distinguish potential patient populations based on genetic classification for stratification into checkpoint inhibitor clinical trials.
Oncoimmunology. 2018 Sep 11;7(12):e1475873. doi: 10.1080/2162402X.2018.1475873. eCollection 2018.
Profiling targetable immune checkpoints in osteosarcoma.
McEachron TA1,2,3, Triche TJ2,4, Sorenson L1, Parham DM4, Carpten JD1,2.
1
Department of Translational Genomics.
2
Norris Comprehensive Cancer Center.
3
Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
4
Department of Pathology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Osteosarcomas are aggressive bone tumors for which therapeutic advances have not improved over several decades. Unlike most pediatric tumors, the osteosarcoma genome is remarkably unstable, characterized by numerous copy number alterations and chromosomal structural aberrations. In this study, we asked if the targetable immune checkpoints CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3) and IDO1 are impacted by copy number alterations in osteosarcoma. Of the 215 osteosarcoma samples investigated, PD-L1/PD-L2, B7-H3 and IDO1 were independently gained at frequencies of approximately 8-9%, with a cumulative frequency of approximately 24%. RNA sequencing data from two independent cohorts revealed that B7-H3 is the most highly expressed immune checkpoint gene among the four investigated. We also show that IDO1 is preferentially expressed in pediatric solid tumors and that increased protein expression of B7-H3 and IDO1 are significantly associated with inferior survival in patient samples. Using human osteosarcoma cell lines, we demonstrate that IDO1 is gained in MG63 and G292 cells and that the IDO1 inhibitor, epacadostat, inhibits the enzymatic activity of IDO1 in a dose-dependent manner in these cells. Together, these data reveal the genomic and transcriptomic profiles of PD-L1, PD-L2, B7-H3 and IDO1 in osteosarcoma and identifies a potential context for targeted immunotherapeutic intervention in a subset of patients. |
