https://openworks.mdanderson.org/sumexp22/1074/thumbnail.jp

Banjo, Oluwatosin

Jiang, Xin Ru

Rezvani, Katy, MD, PhD

English

OpenWorks @ MD Anderson

IntroductionNatural killer (NK) cells are integral to the innate immune system and function to immediately recognize and lyse virally infected cells and tumor cells1,4. NK cell therapy is largely and solely directed towards liquid tumors rather than solid tumors1,4. Solid tumors, including glioblastoma and pancreatic ductal adenocarcinoma, exhibit severe tumor hypoxia and maintain a suppressive tumor microenvironment through the secretion of NK sensitive-inhibitory cytokines1,4. Conclusions• Oncolytic viruses enhance the NK cell killing response of solid tumors. • Dual Knockout NK Cells + Virally pretreated tumors exhibit the greatest NK cell tumor lysis. • NK cells exhibit memory-like behavior upon infected tumor preexposure.References1. Chambers, et al. (2019). Immunometabolic Dysfunction of Natural Killer Cells Mediated by the Hypoxia-CD73 Axis in Solid Tumors. Frontiers in Molecular Biosciences 6.2. Ferrucci, P.F , et al.. (2021). Talimogene Laherparepvec (T-VEC): An Intralesional Cancer Immunotherapy for Advanced Melanoma. Cancers 13, 1383.3. Fueyo, J., et al. (2003). Preclinical Characterization of the Antiglioma Activity of a Tropism-Enhanced Adenovirus Targeted to the Retinoblastoma Pathway. JNCI: Journal of the National Cancer Institute 95, 652–660. https://doi.org/10.1093/jnci/95.9.652.4. Habif, G , et al. (2019). Targeting natural killer cells in solid tumors. Cell Mol Immunol 16, 415–422.5. Han, J., , et al. (2015). TGFβ Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response. Cancer Research 75, 5273–5282.6. Lang, F.F , et al. (2018). Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. J Clin Oncol 36, 1419–1427.Exploring the Effects of Oncolytic Viruses on the NK Cell Killing of Solid Tumors Oluwatosin Banjo1,2, Xin Ru Jiang2, Katy Rezvani, MD, PhD2Wellesley College1, Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center2Experimental Questions and Results:1. Can oncolytic viruses stimulate NK cell killing of solid tumors?2. How do oncolytic viruses enhance NK cell killing?3. Why does the TGF-beta knockout + virally pre-treated tumor cells exhibit the greatest NK cell killing response?Future Directions• Optimization of the TGF-beta pretreatment assay to better understand the mechanism behind the dual knockout enhanced NK cell tumor lysis. • ATAQ Seq and RNA Seq to understand changes in gene expression at different timepoints within our preexposure assay.Figure 1: NK+Virus increases the cytotoxicity of NK cells against pancreatic tumor cells (PDAC). Day 3 Incucyte fluorescence imaging of  BXPC3. 1:10 effector to target ratio. Green fluorescence highlights live tumor cells and red, the dead cell stain. delta24-RGD, 0.5 MOI.Figure 4: Combination of virus and dual knockout (KO) NK cells improves survival in vivo. Survival analysis of mice injected with GSC8-11, Δ24RGD, and NK cells, respectively. Dual Knockout indicates lack of TGF-beta and NR3C1 Glucocorticoid receptor. n=10. Figure 5: NK cells pre-exposed to virally infected tumors exhibit memory like-behavior, identify and effectively kill uninfected tumors. XCelligence of PATC148. oHSV tumor pretreatment, 2 MOI. 4:1 effector to target ratio. Figure 6: Wild-type (WT) and Knockout (KO) NK cell killing is unaffected by TGF-beta pretreatmentIncucyte: red Integrated Intensity of GSC8-11. Δ24RGD tumor pretreatment, 0.25 MOI. TGF-𝛽 is an immunosuppressive cytokine released by tumor cells into the microenvironment and generally functions as an inhibitory response to innate immune response of NK cells5.Oncolytic viruses are genetically-engineered viruses to specifically target and infect tumor cells and rather than normal cells. This includes ‘Oncolytic-Herpes Simplex Virus (oHSV)’ and ‘Δ24RGD (Adenovirus)2,3,6.’Figure 7: TGF-beta pretreatment reduces NK cell anti-tumor killingIncucyte: red Integrated Intensity of GSC8-11. 1:2 effector to target ratio. Δ24RGD tumor pretreatment, 0.05 MOI. Viral Pretreatment of Tumor CellsInfected Tumor Preexposure AssayTGF-beta - NK Cell Pretreatment and Titer AssayMethodsFigure 3: Combination of NK and oHSV demonstrates synergistic killing of pancreatic tumor cells (PATC148). XCelligence of PATC148. oHSV tumor pretreatment, 0.01 MOI. 2:1 effector to target ratio. Figure 2: Combination of NK and delta24RGD demonstrates synergistic killing of glioblastoma stem cells (GSC8-11). Incucyte, red Integrated Intensity of GSC8-11. Δ24RGD tumor pretreatment, 0.05 MOI. 1:2 effector to target ratio. AcknowledgementThank you to Cheryl, Dr. Rezvani, and all members of the Rezvani lab for their help, support, and mentorship. 

Exploring the Effects of Oncolytic Viruses on the NK Cell Killing of Solid Tumors

https://openworks.mdanderson.org/cgi/viewcontent.cgi?article=1074&context=sumexp22

Exploring the Effects of Oncolytic Viruses on the NK Cell Killing of Solid Tumors

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