The Research Institute at Nationwide Children's Hospital Archives

2018

Scholar Grant

Dean Lee

Columbus, OH

Engineered NK cells to enable immunotherapy of pediatric solid tumors

Specific Aim 1: Determine if NK cell-intrinsic SMAD3 suppression improves adoptive immunotherapy against TGFß-expressing brain tumors and sarcomas.
Outcomes: We expect that SMAD3 deficiency will correlate with increased tumor control and survival in the presence of tumors having high TGFß-suppressive TME. SMAD3-deficiency may alter the phenotype or function of NK cells in other ways such that NK cells with SMAD3 deficiency may not be superior for tumors that have low TGFß TME. We expect that TGFß-resistant NK cells will secrete higher levels of cytokines in the tumor leading to greater crosstalk with adaptive immunity and an altered immune contexture.

Specific Aim 2: Assess the impact of TGFBR1, FKBP12, and AHR deletion on host-TME suppression of NK cell function and their utility as knock-in sites.
Outcomes: We expect that suppressing interferon response elements and enhancing cell targeting will enable higher lentiviral transduction efficiency. We also expect insertion of transgenes into suppressive-pathway genes using CRIPSR targeting will allow positive selection of transgene(GFP)+ NK cells and promote stable transgene expression.

Specific Aim 3: Determine the effect of CAR and chemokine expression on anti-tumor efficacy of NK cells.
Outcomes: We expect that suppressive gene-disrupted and CAR-target NK cells will have superior efficacy in tumor control.

The above research will have direct translational benefit to pediatric cancer in developing optimal NK cells for immuotheray of pediatric sarcomas and brain tumors. We will test genetic and non-genetic manipulations to enhance NK cell homing, targeting, and survival in the tumor microenvironment.

Lay Summary:
This research will develop new treatments for cancer by testing new approaches that help a patient’s own cancer-fighting “natural killer” cells (NK cells)
– find cancer
– overcome cancer evasion mechanisms
– kill cancer.

2018

Young Investigator

Ryan Roberts

Columbus, OH

Further defining specific osteosarcoma-lung cell interactions that drive metastatic colonization

Our laboratory seeks to make osteosarcoma metastasis preventable or amenable to effective treatments. Our previous studies identified a specific signaling pathway that gets erroneously activated in osteosarcoma cells. Activation of this “delta-Np63” pathway turns on a set of genes that drive metastasis, especially two cell-cell communication genes called IL6 and CXCL8. Our data suggest that IL6 and CXCL8 stimulate normal lung cells to behave in a way that helps the tumor cells grow within the lung, probably by producing growth factors or other signals that stimulate proliferation and survival of the tumor cells. This could occur in a sort of “loop,” where the tumor cells produce IL6 and CXCL8, stimulating production of growth factors by the lung cells, which in turn stimulate production of IL6 and CXCL8 by the tumor cells, causing a sort of feed-forward amplification loop. Indeed, our preliminary data suggest that such a signaling loop exists. This proposal seeks to identify these lung-derived growth factors. Doing so will facilitate further investigation which may help us to target those factors critical for tumor cell survival in patients.

The second part of this project will leverage our findings to explore the ways in which tumor cells, even within the same tumor, differ from each other. Using very exciting new technologies, we have shown that only a very small group of cells within an osteosarcoma cell line exhibit this ?Np63/IL6/CXCL8-expressing signature—a finding that took us a bit by surprise. This raises the possibility that ?Np63/IL6/CXCL8 expression identifies a small group of “metastasis-initiating cells” within a cell line or within a tumor. Within this proposal, we will also validate those findings and determine whether the responses to signals from lung cells (that we previously described) occur in all of the tumor cells, or just in a subpopulation of “metastasis-initiating cells.”