RT Journal Article
SR Electronic
T1 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
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e005871
DO 10.1136/jitc-2022-005871
VO 11
IS 1
A1 Viktoria Marquardt
A1 Johanna Theruvath
A1 David Pauck
A1 Daniel Picard
A1 Nan Qin
A1 Lena Blümel
A1 Mara Maue
A1 Jasmin Bartl
A1 Ulvi Ahmadov
A1 Maike Langini
A1 Frauke-Dorothee Meyer
A1 Allison Cole
A1 Joselyn Cruz-Cruz
A1 Claus M Graef
A1 Matthias Wölfl
A1 Till Milde
A1 Olaf Witt
A1 Anat Erdreich-Epstein
A1 Gabriel Leprivier
A1 Ulf Kahlert
A1 Anja Stefanski
A1 Kai Stühler
A1 Stephen T Keir
A1 Darell D Bigner
A1 Julia Hauer
A1 Thomas Beez
A1 Christiane B Knobbe-Thomsen
A1 Ute Fischer
A1 Jörg Felsberg
A1 Finn K Hansen
A1 Rajeev Vibhakar
A1 Sujatha Venkatraman
A1 Samuel H Cheshier
A1 Guido Reifenberger
A1 Arndt Borkhardt
A1 Thomas Kurz
A1 Marc Remke
A1 Siddhartha Mitra
YR 2023
UL http://jitc.bmj.com/content/11/1/e005871.abstract
AB Background 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.Methods 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.Results 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.Conclusion 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.Data are available upon reasonable request.