MODL-28. IMMUNE PRIMING WITH INTERFERON-Γ COMBINED WITH EPIGENETIC MODULATION IN PEDIATRIC BRAIN TUMORS

Autor: Andrew J. Mhyre, James M. Olson, Alyssa Noll, Shelli M. Morris, Erin E. Crotty, Ken Brasel, Emily J. Girard
Rok vydání: 2020
Předmět:
Zdroj: Neuro-Oncology
ISSN: 1523-5866
1522-8517
DOI: 10.1093/neuonc/noaa222.601
Popis: Systemic interferon-γ (IFNγ) has been shown to induce major histocompatibility complex class I (MHC-I) and T cell infiltration in solid tumors in adult patients, demonstrating a potential strategy to abrogate tumor-intrinsic mechanisms of immune escape. Pediatric brain tumors (PBT) may be particularly sensitive to this approach but have a paucity of immunogenic tumor antigens for presentation on MHC-I. Decitabine and other DNA methyltransferase (DNMT) inhibitors promote expression of oncofetal antigens and endogenous immune responses through epigenetic alterations. We tested the convergence of these immune priming mechanisms using a novel combination of IFNγ and decitabine across a spectrum of PBT. Primary human cell lines (Med-411FH, PBT-05FH, GBM-511FH, CCHMC-GBM-1, CCHMC-GBM-4, ATRT-310FH) and murine transgenic models were treated with IFNγ alone or in combination with decitabine and evaluated expression of cell surface MHC-I and PD-L1, interferon response genes (ISGs), and oncofetal antigens. PBT showed exquisite sensitivity to IFNγ, increasing expression of MHC-1/PD-L1 along with ISGs (TAP1, MX1, IRF1). Decitabine enhanced IFNγ-induced gene expression of oncofetal antigens NY-ESO-1 and MAGE-A1. In a medulloblastoma flank tumor model, MHC-I was increased by 40-fold following intraperitoneal IFNγ treatment (p=0.01), with a 3-fold increase in PD-L1 (p=0.005) compared to untreated controls. Effect on CD8+ T cell killing and validation in humanized models is ongoing. Immune priming of PBT with IFNγ is feasible and results in more substantial MHC-I upregulation compared to hypomethylating agents alone. These results provide a strong rationale for priming prior to checkpoint inhibition as a compelling therapeutic strategy in immunologically-quiescent PBT.
Databáze: OpenAIRE
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