Tumor-Infiltrating Lymphocytes in Glioblastoma Are Associated with Specific Genomic Alterations and Related to Transcriptional Class

• Authors: W. Caleb Rutledge, Emory University; Jun Kong, Emory University; Jingjing Gao, Emory University; David Gutman, Emory University; Lee Cooper, Emory University; Christina Appin, Emory University; Yuna Park, Emory University; Lisa Scarpace, Henry Ford Hospital; Tom Mikkelsen, Henry Ford Hospital; Mark L. Cohen, Case Western Reserve University; Kenneth D. Aldape, University of Texas; Roger E. McLendon, Duke University; Norman L. Lehman, Ohio State University; C. Ryan Miller, University of North Carolina; Matthew Schniederjan, Emory University; Cameron W. Brennan, Memorial Sloan Kettering Cancer Center; Joel H. Saltz, Emory University; Carlos Moreno, Emory University; Daniel Brat, Emory University
• Journal Title: Clinical Cancer Research
• Volume: Volume 19, Number 18
• Publisher: American Association for Cancer Research | 2013-09-15, Pages 4951-4960
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/1078-0432.CCR-13-0551
• Subjects: Health Sciences, Oncology; Health Sciences, Pathology; Biology, Biostatistics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; REGULATORY T-CELLS; COLORECTAL-CANCER; PROGNOSTIC VALUE; SURVIVAL; GLIOMA; EXPRESSION; IDH1; IMMUNOTHERAPY; ASTROCYTOMAS; COMPARTMENT

Abstract

Purpose: Tumor-infiltrating lymphocytes (TIL) have prognostic significance in many cancers, yet their roles in glioblastoma have not been fully defined. We hypothesized that TILs in glioblastoma are associated with molecular alterations, histologies, and survival. Experimental Design: We used data from The Cancer Genome Atlas (TCGA) to investigate molecular, histologic, and clinical correlates of TILs in glioblastomas. Lymphocytes were categorized as absent, present, or abundant in histopathologic images from 171 TCGA glioblastomas. Associations were examined between lymphocytes and histologic features, mutations, copy number alterations, CpG island methylator phenotype, transcriptional class, and survival. Wevalidated histologic findings usingCD3Ggene expression. Results: Wefound a positive correlation between TILs and glioblastomas with gemistocytes, sarcomatous cells, epithelioid cells, and giant cells. Lymphocytes were enriched in the mesenchymal transcriptional class and strongly associated with mutations in NF1 and RB1. These mutations are frequent in the mesenchymal class and characteristic of gemistocytic, sarcomatous, epithelioid, and giant cell histologies. Conversely, TILs were rare in glioblastomas with small cells and oligodendroglioma components. Lymphocytes were depleted in the classical transcriptional class and in EGF receptor (EGFR)-amplified and homozygous PTEN-deleted glioblastomas. These alterations are characteristic of glioblastomas with small cells and glioblastomas of the classical transcriptional class. No association with survival was shown. Conclusions: TILs were enriched in glioblastomas of the mesenchymal class, strongly associated with mutations in NF1 and RB1 and typical of histologies characterized by these mutations. Conversely, TILs were depleted in the classical class, EGFR-amplified, and homozygous PTEN-deleted tumors and rare in histologies characterized by these alterations.