Zhao and Chen et al. analyzed tumor and blood samples, as well as clinical data from 66 glioblastoma patients treated with anti-PD-1 upon recurrence after standard therapy, and found that response to anti-PD-1 correlated with better overall survival. MAPK pathway (BRAF, PTPN11) mutations were enriched in responders and PTEN mutations in non-responders, while the overall mutational burden did not differ. As indicated by changes in the mutational landscape, TCR clonal diversity, and immunosuppressive gene profiles, non-responders showed primary resistance to anti-PD-1, while responders acquired resistance following immunoediting.
Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
Author Info: (1) Department of Systems Biology, Columbia University, New York, NY, USA. Department of Biomedical Informatics, Columbia University, New York, NY, USA. (2) Department of Systems B
Author Info: (1) Department of Systems Biology, Columbia University, New York, NY, USA. Department of Biomedical Informatics, Columbia University, New York, NY, USA. (2) Department of Systems Biology, Columbia University, New York, NY, USA. (3) Department of Pediatrics, Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, NY, USA. (4) Department of Pediatrics, Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, NY, USA. (5) Department of Systems Biology, Columbia University, New York, NY, USA. Department of Biomedical Informatics, Columbia University, New York, NY, USA. (6) Department of Systems Biology, Columbia University, New York, NY, USA. Department of Biomedical Informatics, Columbia University, New York, NY, USA. (7) Department of Pediatrics, Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, NY, USA. (8) Department of Pediatrics, Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, NY, USA. (9) Department of Neurosurgery, Columbia University, New York, NY, USA. (10) Department of Neurosurgery, Columbia University, New York, NY, USA. (11) Department of Systems Biology, Columbia University, New York, NY, USA. (12) Department of Systems Biology, Columbia University, New York, NY, USA. (13) Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (14) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (15) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (16) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (17) Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (18) Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (19) Department of Neurological Surgery, Oregon Health & Sciences University, Portland, OR, USA. (20) Department of Biomedical Informatics, Columbia University, New York, NY, USA. (21) Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. (22) Department of Neurosurgery, Columbia University, New York, NY, USA. (23) Department of Medicine, Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA. (24) Department of Biomedical Informatics, Columbia University, New York, NY, USA. (25) Department of Neurology, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. fi2146@cumc.columbia.edu. (26) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Adam.Sonabend@nm.org. (27) Department of Systems Biology, Columbia University, New York, NY, USA. rr2579@cumc.columbia.edu. Department of Biomedical Informatics, Columbia University, New York, NY, USA. rr2579@cumc.columbia.edu.
