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000186754 0247_ $$2doi$$a10.1136/jitc-2022-005871
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000186754 1001_ $$0P:(DE-He78)da540cf439735fb1385a3a90933baa23$$aMarquardt, Viktoria$$b0
000186754 245__ $$aTacedinaline (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.
000186754 260__ $$aLondon$$bBioMed Central$$c2023
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000186754 520__ $$aWhile 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.
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000186754 650_7 $$2Other$$aBrain Neoplasms
000186754 650_7 $$2Other$$aCytotoxicity, Immunologic
000186754 650_7 $$2Other$$aImmunotherapy
000186754 650_7 $$2Other$$aMacrophages
000186754 650_7 $$2Other$$aPhagocytosis
000186754 7001_ $$aTheruvath, Johanna$$b1
000186754 7001_ $$0P:(DE-He78)964e19ad88fd6ff751ae2c10599ad7cc$$aPauck, David$$b2
000186754 7001_ $$0P:(DE-He78)2d0b899984e41ffa8cb15d799d32afd1$$aPicard, Daniel Joseph$$b3$$udkfz
000186754 7001_ $$0P:(DE-He78)a05fe89e8d9ccc1fbd56df77464c7856$$aQin, Nan$$b4
000186754 7001_ $$0P:(DE-He78)aa640ee2ad93f62391334644cfa44c61$$aBlümel, Lena$$b5
000186754 7001_ $$0P:(DE-He78)169f4992859d52c4184d9ab9ce445d1d$$aMaue, Mara$$b6$$udkfz
000186754 7001_ $$0P:(DE-He78)0b115428d6170ebe021af308ed2a0cf1$$aBartl, Jasmin$$b7
000186754 7001_ $$0P:(DE-He78)87bc8fe0f11339b1fac47821a539bdb3$$aAhmadov, Ulvi$$b8$$udkfz
000186754 7001_ $$0P:(DE-HGF)0$$aLangini, Maike$$b9
000186754 7001_ $$0P:(DE-He78)59ffe2957ee9f9009e7d4ec650023f47$$aMeyer, Frauke-Dorothee$$b10$$udkfz
000186754 7001_ $$aCole, Allison$$b11
000186754 7001_ $$aCruz-Cruz, Joselyn$$b12
000186754 7001_ $$aGraef, Claus M$$b13
000186754 7001_ $$aWölfl, Matthias$$b14
000186754 7001_ $$aMilde, Till$$b15
000186754 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b16$$udkfz
000186754 7001_ $$aErdreich-Epstein, Anat$$b17
000186754 7001_ $$0P:(DE-HGF)0$$aLeprivier, Gabriel$$b18
000186754 7001_ $$aKahlert, Ulf$$b19
000186754 7001_ $$aStefanski, Anja$$b20
000186754 7001_ $$aStühler, Kai$$b21
000186754 7001_ $$aKeir, Stephen T$$b22
000186754 7001_ $$aBigner, Darell D$$b23
000186754 7001_ $$aHauer, Julia$$b24
000186754 7001_ $$aBeez, Thomas$$b25
000186754 7001_ $$0P:(DE-HGF)0$$aKnobbe-Thomsen, Christiane B$$b26
000186754 7001_ $$aFischer, Ute$$b27
000186754 7001_ $$0P:(DE-HGF)0$$aFelsberg, Jörg$$b28
000186754 7001_ $$aHansen, Finn K$$b29
000186754 7001_ $$aVibhakar, Rajeev$$b30
000186754 7001_ $$aVenkatraman, Sujatha$$b31
000186754 7001_ $$aCheshier, Samuel H$$b32
000186754 7001_ $$0P:(DE-HGF)0$$aReifenberger, Guido$$b33
000186754 7001_ $$0P:(DE-HGF)0$$aBorkhardt, Arndt$$b34
000186754 7001_ $$aKurz, Thomas$$b35
000186754 7001_ $$0P:(DE-He78)a244aa021112b9002419791434bbc71c$$aRemke, Marc$$b36$$udkfz
000186754 7001_ $$00000-0002-1829-7856$$aMitra, Siddhartha$$b37
000186754 773__ $$0PERI:(DE-600)2719863-7$$a10.1136/jitc-2022-005871$$gVol. 11, no. 1, p. e005871 -$$n1$$pe005871$$tJournal for ImmunoTherapy of Cancer$$v11$$x2051-1426$$y2023
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