Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and enriched in the mesenchymal transcriptional class 公开

Rutledge, William Caleb (2013)

Permanent URL: https://etd.library.emory.edu/concern/etds/n296wz234?locale=zh
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Abstract

Glioblastoma (GBM) is a highly malignant astrocytoma with an extremely poor prognosis. While tumor-infiltrating lymphocytes (TILs) have prognostic significance and potential therapeutic relevance in many cancers, their roles in GBM have not been fully defined. We hypothesized that TILs in GBM are associated with specific molecular alterations and histologies and variably contribute to the host immune response.

We used publicly available data from The Cancer Genome Atlas (TCGA) to investigate clinical, molecular, and histologic correlates of TILs in GBM. Lymphocytes were categorized as absent (0), present (1+), or abundant (2+) in digitized, whole slide histopathologic images from 171 TCGA GBM cases. TILs were absent (0) in 93 cases (54%), present (1+) in 59 cases (35%), and abundant (2+) in 19 cases (11%). Associations were examined between TILs and histologic features, mutations, copy number alterations, G-CIMP status, gene expression class, and clinical outcome.

We found a positive correlation between TILs and GBMs with abundant gemistocytes, sarcomatous cells, epithelioid cells, and giant cells. Conversely, TILs were rare in GBMs characterized by small cells and oligodendroglioma components. TILs were enriched in the mesenchymal transcriptional class, with 71% of cases containing abundant (2+) TILs within this class. TILs were strongly associated with mutations in NF1 and RB1 and trended towards significance for TP53. These mutations are frequent in the mesenchymal transcriptional class and characteristic of gemistocytic, sarcomatous, epithelioid, and giant cell histologic subtypes of GBM. In contrast, TILs were depleted in EGFR-amplified and homozygous PTEN-deleted GBMs. No association with survival was demonstrated.

We found that TILs were enriched in GBMs in the mesenchymal transcriptional class, strongly associated with mutations in NF1 and RB1, and typical of histologic subtypes characterized by these mutations. TILs were depleted in EGFR-amplified and PTEN-deleted GBMs, as well as those with small cell and oligodendroglioma components. Immunogenic mechanisms underlying these molecular associations remain to be further explored.

Table of Contents

I. INTRODUCTION AND BACKGROUND

II. METHODS

III. RESULTS

IV. DISCUSSION/CONCLUSION

V. REFERENCES

VI. TABLES AND FIGURES

TABLE 1. Tumor-infiltrating lymphocytes are associated with specific histopathologic features in GBM.

TABLE 2. Tumor-infiltrating lymphocytes are associated with specific mutations in glioblastoma.

TABLE 3. Tumor-infiltrating lymphocytes are depleted in EGFR-amplified and homozygous PTEN-deleted tumors.

TABLE 4. Tumor-infiltrating lymphocytes are enriched in the mesenchymal class.

FIGURE 1. Tumor-infiltrating lymphocytes in glioblastoma do not vary according to age.

FIGURE 2. Tumor-infiltrating lymphocytes are enriched in glioblastomas with sarcomatous cells (A), gemistocytes (B), epithelioid cells (not shown), and giant cells (C). TILs are depleted in GBMs with oligodendroglial cells (D) and small cells.

FIGURE 3. Tumor-infiltrating lymphocytes are not associated with improved survival.

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