Impact of Hypoxic Conditions on Natural Killer Cell Cytokine Secretion Paul McClure MS2, Upasana Arvindam, Dr. Jeffrey Miller MD Department of Medicine, Division of Hematology, Oncology, and Transplantation University of Minnesota, Minneapolis, MN 55455, USA
16
Embed
Impact of Hypoxic Conditions on Natural Killer Cell ...€¦ · NK Cells -Background •Main duties: killing virally infected cells, immune surveillance for cancer –NK Cells kill
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Impact of Hypoxic Conditions on Natural Killer Cell Cytokine Secretion
Paul McClure MS2, Upasana Arvindam, Dr. Jeffrey Miller MDDepartment of Medicine, Division of Hematology, Oncology, and TransplantationUniversity of Minnesota, Minneapolis, MN 55455, USA
NK Cells - Background
• Main duties: killing virally infected cells, immune surveillance for cancer– NK Cells kill cells that do not express MHC-I or that do
express other markers of stress• No priming or prior exposure required, but NK cell
NK cells were cultured with K562 cells for 24 hours following 1 week incubation in AVATAR
NK Cell Phenotype Heterogeneity• CD56: the canonical marker
used for differentiating NK cell subsets
• Other considerations: proliferative capacity vs. cytotoxic function, NK cell ‘licensing’, unique lineages of NK Cells (NK92, NK101, etc.)
Ki-67 expression in 12% O2
Ki-67 expression in 1% O2
NK Cell Marker Expression in Hypoxia
Increased expression of
CD69 is significant due to
relationship with HIF-1a
Greater % of CD56dim
vs. CD56bright NK cells
in hypoxic conditions.
12% O2 (Blood) 1% O2 (Solid Tumor)
Other markers of
interest: Ki-67,
CD96, TIGIT etc.
Cytotoxicity is Impaired in HypoxiaNK Cell mediated killing of K562 target cells is dramatically impaired in conditions mirroring a solid tumor relative to peripheral blood or bone marrow
Discussion: Looking Beyond NK Cells
• The role of TGF-beta in immunosuppression is still largely unknown in vivo
• How to sustain proliferation and function of NK cells in solid tumors
Conclusion
• NK-cell cytokine production is highest in conditions mirroring those found in bone marrow, lowest in those representative of a solid tumor
• NK Cells do not produce significant amounts of TGFbin any of the studied conditions but K562 cells significantly increase their secretion in hypoxic conditions
Future Directions/Implications• Ongoing co-culture experiments with Regulatory T-
Cells and Myeloid Derived Suppressor Cells• Developing induced NK (iNK) cells that preserve
cytokine secretion and function in hypoxia• What is the role of cytokines in NK cell exhaustion?• Microscopic characterization of NK cell degranulation
and cytotoxicity in various incubation conditions
AcknowledgementsMiller LabUpasana ArvindamDr. Pippa KennedyBri EttestadPeter HowardDr. Martin FelicesDr. Jeffrey MillerCytokine Reference Lab for Luminex analysis
NIH Summer T35 ProgramDr. Dan MuellerStephanie Krischuk
All the faculty who came to present their work over the course of the summer