Poster abstracts

Poster number 103 submitted by Ezgi Elmas

Discovering novel pathways to overcome immunosuppression in NK cells Against High-grade Gliomas

Ezgi Elmas (MCDB), Yasemin Sezgin (Nationwide Childrens Hospital), Meisam Naeimi Kararoudi (The Ohio State University), Dean A. Lee (The Ohio State University)

Abstract:
Glioblastoma multiforme (GBM) is one of the most devastating and lethal brain tumors in humans. Although more common in adults, GBM is one of the leading causes of cancer-related death in children. Currently, there is no cure for children with GBM. Adaptive cell therapies such as Natural killer (NK) cell immunotherapy have been proposed as potential treatments for GBM. NK cells can recognize and kill GBM without prior exposure, and they do not cause acute graft versus host disease (GvHD) after infusion, unlike T-cells, making them excellent candidates to destroy GBM cells. NK cells can recognize GBM ligands (MICA, MICB) through its natural cytotoxicity receptor, natural killer group protein 2 family member D (NKG2D) receptor. However, Tumor growth factor beta (TGF-b) decreases NKG2D expression and causes NK cells to have reduced cytotoxic activity, an exhausted phenotype, and less tumor infiltration in the glioma tumor microenvironment. TGF-b in high-grade gliomas is crucial in hindering anti-tumor immune response and evading immune cell killing. TGF-b, secreted by GBM cells, binds to TGF-b receptors on NK cells and initiates suppressive signaling pathways. Therefore, we originally postulated that SMAD3 inhibition would enhance NK cell cytotoxicity against GBM in the presence of TGF-b. We showed that inhibition of SMAD3 in NK cells did not improve the NK cell-killing activity against GBM. This led us to hypothesize that SMAD3-independent (non-canonical) signaling suppresses NK cell activity against GBM. We performed RNA and ChIP-seq experiments to identify canonical and non-canonical TGF-b signaling genes. We discovered several genes such as HOBIT (ZNF683) involved in the non-canonical TGBF-b signaling. Our result show that HOBIT can directly mediate TGF-b signaling and have a functional role in TGF-b immunosuppressive activity in NK cells.

Keywords: Natural Killer cells, Glioblastoma, Tumor growth factor beta