TY  - JOUR
AU  - Marquardt, Viktoria
AU  - Theruvath, Johanna
AU  - Pauck, David
AU  - Picard, Daniel Joseph
AU  - Qin, Nan
AU  - Blümel, Lena
AU  - Maue, Mara
AU  - Bartl, Jasmin
AU  - Ahmadov, Ulvi
AU  - Langini, Maike
AU  - Meyer, Frauke-Dorothee
AU  - Cole, Allison
AU  - Cruz-Cruz, Joselyn
AU  - Graef, Claus M
AU  - Wölfl, Matthias
AU  - Milde, Till
AU  - Witt, Olaf
AU  - Erdreich-Epstein, Anat
AU  - Leprivier, Gabriel
AU  - Kahlert, Ulf
AU  - Stefanski, Anja
AU  - Stühler, Kai
AU  - Keir, Stephen T
AU  - Bigner, Darell D
AU  - Hauer, Julia
AU  - Beez, Thomas
AU  - Knobbe-Thomsen, Christiane B
AU  - Fischer, Ute
AU  - Felsberg, Jörg
AU  - Hansen, Finn K
AU  - Vibhakar, Rajeev
AU  - Venkatraman, Sujatha
AU  - Cheshier, Samuel H
AU  - Reifenberger, Guido
AU  - Borkhardt, Arndt
AU  - Kurz, Thomas
AU  - Remke, Marc
AU  - Mitra, Siddhartha
TI  - Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation.
JO  - Journal for ImmunoTherapy of Cancer
VL  - 11
IS  - 1
SN  - 2051-1426
CY  - London
PB  - BioMed Central
M1  - DKFZ-2023-00098
SP  - e005871
PY  - 2023
AB  - While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway.We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models.CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment ('eat-me') signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice.Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.
KW  - Brain Neoplasms (Other)
KW  - Cytotoxicity, Immunologic (Other)
KW  - Immunotherapy (Other)
KW  - Macrophages (Other)
KW  - Phagocytosis (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36639156
DO  - DOI:10.1136/jitc-2022-005871
UR  - https://inrepo02.dkfz.de/record/186754
ER  -