Journal Article

DKFZ-2020-00444

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas.

Aslan, K. (First author)DKFZ* ; Turco, V.DKFZ* ; Blobner, J.DKFZ* ; Sonner, J.DKFZ* ; Liuzzi, A. R. ; Núñez, N. G. ; De Feo, D. ; Kickingereder, P. ; Fischer, M.DKFZ* ; Green, E.DKFZ* ; Sadik, A.DKFZ* ; Friedrich, M.DKFZ* ; Sanghvi, K.DKFZ* ; Kilian, M.DKFZ* ; Cichon, F.DKFZ* ; Wolf, L.DKFZ* ; Jähne, K.DKFZ* ; von Landenberg, A.DKFZ* ; Bunse, L.DKFZ* ; Sahm, F.DKFZ* ; Schrimpf, D.DKFZ* ; Meyer, J.DKFZ* ; Alexander, A.DKFZ* ; Brugnara, G. ; Röth, R. ; Pfleiderer, K.DKFZ* ; Niesler, B. ; von Deimling, A.DKFZ* ; Opitz, C.DKFZ* ; Breckwoldt, M.DKFZ* ; Heiland, S. ; Bendszus, M. ; Wick, W.DKFZ* ; Becher, B. ; Platten, M. (Last author)DKFZ*

2020
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-020-14642-0

Abstract: Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.

Note: #EA:D170#LA:D170# / HI-TRON / #DKFZ-MOST-Ca188#

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Contributing Institute(s):

1. KKE Neuroimmunologie und Hirntumorimmunologie (D170)
2. Metabolischer Crosstalk bei Krebserkrankungen (B350)
3. KKE Neuropathologie (B300)
4. KKE Neuroonkologie (B320)
5. DKTK HD zentral (HD01)

Research Program(s):

1. 314 - Tumor immunology (POF3-314) (POF3-314)

Appears in the scientific report 2020

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