Glioma escape signature and clonal development under immune pressure.
Animals
Brain Neoplasms
/ genetics
Cell Line, Tumor
Clonal Evolution
/ genetics
DNA-Binding Proteins
/ deficiency
Female
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Glioma
/ genetics
Humans
Immunocompetence
Immunocompromised Host
Mice
Mice, Inbred C57BL
Mice, Knockout
Pore Forming Cytotoxic Proteins
/ deficiency
Tumor Escape
/ genetics
Tumor Microenvironment
/ genetics
Brain cancer
Immunology
Oncology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 10 2020
01 10 2020
Historique:
received:
02
04
2020
accepted:
24
06
2020
pubmed:
1
7
2020
medline:
26
2
2021
entrez:
1
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32603315
pii: 138760
doi: 10.1172/JCI138760
pmc: PMC7524465
doi:
pii:
Substances chimiques
DNA-Binding Proteins
0
Pore Forming Cytotoxic Proteins
0
Rag2 protein, mouse
0
perforin, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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