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

Abstract

Purpose Tumor-infiltrating lymphocytes (TILs) have prognostic significance in many cancers, yet their roles in glioblastoma (GBM) have not been fully defined. We hypothesized TILs in GBM 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 GBMs. Lymphocytes were categorized as absent, present or abundant in histopathologic images from 171 TCGA GBMs. Associations were examined between lymphocytes and histologic features, mutations, copy number alterations, CpG island methylator phenotype, transcriptional class and survival. We validated histologic findings using CD3G gene expression. Results We found a positive correlation between TILs and GBMs 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 GBMs with small cells and oligodendroglioma components. Lymphocytes were depleted in the classical transcriptional class and in EGFR-amplified and homozygous PTEN-deleted GBMs. These alterations are characteristic of GBMs with small cells and GBMs of the classical transcriptional class. No association with survival was demonstrated. Conclusions TILs were enriched in GBMs 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.

Tumor-infiltrating lymphocytes (TILs) from patients with glioma

“…5 A similar mechanism may be clinically relevant for patients with glioma, supported by the notion that the frequency of mutations in glioma has been associated with stronger T-cell infiltrates. 38 The method described in the current report allows now to reliably expand TIL, that react against autologous glioma cells and to perform tumor DNA exome-sequencing with the subsequent analysis of TIL-defined tumor-associated targets.…”

Coinhibitory Pathways in Immunotherapy for Cancer

“…Escape mechanisms include tumor cell-intrinsic effects such as loss of tumorantigen expression and induction of antiapoptotic pathways, rendering tumors resistant to cytotoxic immunity. Recent investigations have substantiated the concept of cancer immunoediting by demonstrating that genomic tumor alterations and neoantigen load are linked to immune responses (25,26). Alternatively, escape may result from the establishment of an immunosuppressive state in the tumor microenvironment, with the production of indoleamine 2,3-dioxygenase (IDO), vascular endothelial growth factor (VEGF), and TGF-β; the recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs); and the promotion of the expression of coinhibitory molecules such as CTLA-4, PD-1, and PD-L1.…”

Whole Slide Imaging for Analytical Anatomic Pathology and Telepathology: Practical Applications Today, Promises, and Perils

“…66,67 Earlier studies from our department established the role of Ki-67 quantitation in glial neoplasms. 68,69 Recently, using multimodal, multiscale approaches and machine-based classification, researchers have devised ways to mine scanned histologic data on glioblastoma in The Cancer Genome Atlas Project and other sources; the resulting quantitative morphometric analysis findings have been further integrated with molecular data to provide in silico cancer research [70][71][72][73][74][75][76][77][78][79][80] and with radiologic data to provide clinicopathoradiologic correlation. 81 Insights from this work also include findings on the importance of tumor-infiltrating lymphocytes in glioblastoma, 72 and in silico approaches from these studies have uncovered novel findings regarding the regulation of asymmetric cell division in glioblastoma by such mediators as the human Brat ortholog TRIM3.…”