Deacetylated Sialic Acid Inhibit NK Cell Killing Function via Siglec-7/9-Mediated Suppression of NKG2D-DAP10 Signaling

Refractory cancers overexpress Deacetylated-Sialic Acid (DeAc-Sia) on the cell surface, yet the contribution of this glycan to cancer immune evasion is poorly understood. We discovered that cancers with high DeAc-Sia expression co-opt the “Sia-Siglec pathway” to escape killing by NK cells, restricting immune surveillance. Strategies to restore NK cell responsiveness represent a novel approach applicable to multiple cancers. The precise intracellular mechanisms by which these interactions suppress NK function remain a critical gap in current knowledge. Our long-term goal is to identify therapeutic targets that disrupt the inhibitory effects of DeAc-Sia, to treat multiple types of cancer. Achieving this goal requires an understanding of how DeAc-Sia-Siglec interaction inhibits NKG2D-DAP10 signaling for cancer cell survival, highlighting our overall objective. We will test the novel hypothesis that binding of DeAc-Sia to Siglec 7 & 9 decreases NK-mediated cancer cell killing by blocking the activating signal propagated by the NKG2D-DAP10 complex. We have shown that in the presence of elevated levels of DeAc -Sia on the surface of cancer cells engage Siglec 7 & 9, blocking NK killing. As such, it is reasonable to hypothesize that engagement of Siglec 7 & 9 by DeAc-Sia sends an inhibitory signal to the NKG2D-DAP10 complex. This hypothesis is supported by both published research and preliminary data showing that, upon binding of the NK’s Siglec 7 & 9 receptors by DeAc-Sia, there is a significant reduction of lytic granule release, pro-inflammatory cytokines, a reduced expression of both the NKG2D-DAP10 activating complex and the associated proteins in this signaling pathway, but increased expression of the pro-apoptotic factors. The rationale that underlies the proposed research is that strategies that restore NK cell responsiveness through NKG2D-DAP10 activation will advance glycan-based cancer therapies theoretically capable of treating cancers expressing DeAc-Sia. The central hypothesis will be tested by pursuing three specific aims: 1. Determine the role of DeAc Sia/Siglec binding on NKG2D-DAP10 signal transduction 2. Determine the role of DeAc-Sia/Siglec binding on the release of cytotoxic components and cytokines by NKG2D-DAP10 3. Determine the role of Siglec 7 and 9 in the activation of pro-apoptotic factors. The proposed research is innovative because it focuses on understanding how cancers utilize DeAc-Sia to reprogram the NKGD2-DAP10 signaling pathway for NK apoptosis and cancer cell survival. Project Number: 5P20GM135008-05 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Rachel Willand-Charnley | Institution: SOUTH DAKOTA STATE UNIVERSITY, BROOKINGS, SD | Award Amount: $273,651 | Activity Code: P20 | Study Section: ZGM1-RCB-W(C1) View on NIH RePORTER: https://reporter.nih.gov/project-details/11530753