Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy

• Published in: Nature communications Vol. 12; no. 1; p. 352
• Main Authors: Gromeier, Matthias, Brown, Michael C., Zhang, Gao, Lin, Xiang, Chen, Yeqing, Wei, Zhi, Beaubier, Nike, Yan, Hai, He, Yiping, Desjardins, Annick, Herndon, James E., Varn, Frederick S., Verhaak, Roel G., Zhao, Junfei, Bolognesi, Dani P., Friedman, Allan H., Friedman, Henry S., McSherry, Frances, Muscat, Andrea M., Lipp, Eric S., Nair, Smita K., Khasraw, Mustafa, Peters, Katherine B., Randazzo, Dina, Sampson, John H., McLendon, Roger E., Bigner, Darell D., Ashley, David M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 45/91; 631/250/580/1884/2323; 631/67/1922; 692/4028/67/1059/2325; Biomarkers, Tumor - genetics; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Cancer immunotherapy; Clinical trials; Cohort Studies; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Genomic analysis; Genomics - methods; Glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastoma - therapy; Humanities and Social Sciences; Humans; Immune checkpoint; Immunotherapy; Immunotherapy - methods; Inflammation; Inflammation - genetics; multidisciplinary; Mutation; Neoplasm Recurrence, Local; Oncolytic Virotherapy - methods; Outcome Assessment, Health Care - methods; Outcome Assessment, Health Care - statistics & numerical data; Proportional Hazards Models; Science; Science (multidisciplinary); Signatures; Survival; Survival Analysis; Tissue analysis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20469-6

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10–20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence. Recurrent glioblastomas (rGBM) have dismal outcomes, but long-term survival has been observed in subsets of patients after immunotherapy. Here the authors report a positive association between low tumor mutation burden, inflammatory gene signatures, and survival after immunotherapy in rGBM patients.