Glioma escape signature and clonal development under immune pressure
Cecile L. Maire, … , Manfred Westphal, Katrin Lamszus
Cecile L. Maire, … , Manfred Westphal, Katrin Lamszus
Published June 30, 2020
Citation Information: J Clin Invest. 2020;130(10):5257-5271. https://doi.org/10.1172/JCI138760.
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Research Article Immunology Oncology Article has an altmetric score of 2

Glioma escape signature and clonal development under immune pressure

Abstract

Immunotherapeutic strategies are increasingly important in neuro-oncology, and the elucidation of escape mechanisms that lead to treatment resistance is crucial. We investigated the impact of immune pressure on the clonal dynamics and immune escape signature by comparing glioma growth in immunocompetent versus immunodeficient mice. Glioma-bearing WT and Pd-1–/– mice survived significantly longer than immunodeficient Pfp–/– Rag2–/– mice. While tumors in Pfp–/– Rag2–/– mice were highly polyclonal, immunoedited tumors in WT and Pd-1–/– mice displayed reduced clonality with emergence of immune escape clones. Tumor cells in WT mice were distinguished by an IFN-γ–mediated response signature with upregulation of genes involved in immunosuppression. Tumor-infiltrating stromal cells, which include macrophages/microglia, contributed even more strongly to the immunosuppressive signature than the actual tumor cells. The identified murine immune escape signature was reflected in human patients and correlated with poor survival. In conclusion, immune pressure profoundly shapes the clonal composition and gene regulation in malignant gliomas.

Authors

Cecile L. Maire, Malte Mohme, Michael Bockmayr, Krystian D. Fita, Kristoffer Riecken, Daniela Börnigen, Malik Alawi, Antonio Failla, Katharina Kolbe, Svenja Zapf, Mareike Holz, Katrin Neumann, Lasse Dührsen, Tobias Lange, Boris Fehse, Manfred Westphal, Katrin Lamszus

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Figure 9

Clonal heterogeneity in RGB-marked tumors.

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Clonal heterogeneity in RGB-marked tumors. (A) Schematic representation ...
(A) Schematic representation of lentiviral RGB marking of GL261 cells. Fluorescent proteins of the 3 basic colors are mixed at different but highly stable expression intensities so that all perceivable colors are generated. (B) Confocal fluorescence microscopy of RGB-marked GL261 tumors in WT and Pfp–/– Rag2–/– mice. Scale bar: 50 μm. (C) Spherical scatter plot of cells analyzed by flow cytometry. Each data point designates the chromaticity value of a cell. Note the reduced occupancy, i.e., the plot area occupied with data points in WT mice compared with Pfp–/– Rag2–/– mice and compared with the preinjection mix. (D) Quantification of occupancy after multistep dimensionality reduction validates significantly higher clonal contraction in tumors in WT mice than in Pfp–/– Rag2–/– mice, compared with the multiclonal preinjection mix. Box plots with IQR (box), mean (line), and maximum/minimum (whiskers). One-way ANOVA (P = 0.001) with Tukey’s post hoc test; *P < 0.05, ***P = 0.001; n = 4 per mouse group, n = 2 for the preinjection mix.