Friday, May 10, 2024
5/10/2024
Abstract Neutrophils are not often considered as cancer killing immune cells in the same way that natural killer cells, cytotoxic T cells and macrophages. However, the inherent capability of neutrophils to be cytotoxic is clinically evident in diseases of hyperinflammation (such as sepsis) where activated neutrophils contribute to organ failure by destroying otherwise healthy cells and tissues. Therefore, neutrophils possess all the cytolytic machinery needed to be destructive to host tissues and we propose that includes cancer. What is lacking is a clearly defined targeting mechanism that can focus the cytotoxic potential of neutrophils towards cancer cells in a specific and controlled manner. This proposal will present published and preliminary evidence that neutrophils can indeed be successfully targeted to cancer cells leading to a newly described non-apoptotic cancer killing mechanism called trogoptosis. Trogoptosis (Greek: trogo; “gnaw”) is a newly described effector mechanism that brings neutrophils into the discussion of tumor killing immune cells. Trogoptosis is a form of antibody-dependent cellular cytotoxicity (ADCC) that triggers neutrophils to destroy antibody-opsonized tumor targets by forming a transient receptor-mediated synapse between the neutrophil and the tumor target. Killing occurs as a result of the neutrophil gnawing at the tumor plasma membrane and dismembering it into chunks, and is distinct from apoptosis and necrosis. Neutrophils internalize these pieces of tumor cells by phagocytosis and migrate away. Trogoptosis is dependent on the neutrophil beta2 integrin Complement Receptor 3 (CR3; CD11b/CD18; Mac-1). Antibody blockade of CR3, or neutrophils from families with genetic absence of CR3, obviate trogoptosis. Given the relative recency of this discovery, there remains much to be learned about this effector mechanism. A highly selected experimental plan is offered to fit within the budget and timeframe of an R03 yet allow rigorous testing of the hypothesis that neutrophil trogoptosis is a function that can be enhanced by agonists of neutrophil CR3 and augment the efficacy of anti-cancer antibody therapy. This R03 would develop a nascent collaboration between two laboratories with a track record in the use of biomimetic experimental systems to study breast cancer invasion and the function of human neutrophils. The experimental approach will use fibrous gels of varying stiffnesses and ECM composition that reflect differences that exist among various bodily tissues and organs. MDA-231 TNBC will be modeled as single invasive cells (Specific Aim 1) and as 3D spheroids (Specific Aim 2) in testing the trogoptoptic killing by human neutrophils introduced as tumoricidal effector cells. Additional work will determine if neutrophil CR3 is a druggable target that can enhance the effectiveness of neutrophil-dependent tumor killing and thereby potentially serve as an adjuvant to anti-tumor antibody therapy in the clinic. Our overall objective is to demonstrate that human neutrophils can be stimulated to function effectively and specifically as tumoricidal immune cells.
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