wetenschapsdag 2023 | 107 Sessie 3d: Architecturale Hoogstandjes en Chirurgische Laagstandjes x4 Auteurs C.A.N. Sewnath, L. Geerlings, N.L. van der Meijs, S.J. van Vliet, M. van Egmond Abstract titel Neutrophil-mediated tumor cell killing induces uptake of antigens and dendritic cell maturation Background Antibody therapy is a promising strategy for cancer treatment. Unfortunately, many tumors have an immunosuppressive microenvironment, precluding the induction of long-term adaptive immune responses. This immunosuppressive tumor environment can be infiltrated with various immune cells that can secrete antiinflammatory mediators thereby preventing tumor cell killing by other immune cells. Methods Recently, we developed a bi-specific antibody called TrisomAb, which consists of three elements. It can target tumor-associated antigens (binding to tumor cells) and FcαRI (binding of neutrophils) with a functional IgG Fc tail (binding of NK cells and macrophages). Our goal is to investigate if adaptive immune responses can be induced using TrisomAb. Therefore, co-cultures with neutrophils, dendritic cells, tumor cells and TrisomAb were performed. Uptake and activation measurement was done by flow cytometry and migration of fluorescent cells by a multi-mode microplate reader. Furthermore, the cytokine profile of co-cultures were assessed by ELISA. Results Our data showed that TrisomAb recruited and activated neutrophils, which induced tumor cell killing. Co-culture of tumor cells with dendritic cells, neutrophils and TrisomAb resulted in release of tumor antigens by neutrophils and enhanced antigen uptake by dendritic cells. Uptake of tumor antigens by these dendritic cells led to maturation as well as secretion of proinflammatory cytokines that are involved in induction of T cell responses. It was also observed that these activated moDCs migrated towards lymphnode-associated CCL19/CCL21. Conclusion Taken together, neutrophil-mediated killing via TrisomAb leads to tumor cell antigen uptake by dendritic cells. Moreover, tumor antigen uptake by dendritic cells results in activation, migration and subsequent secretion of factors that could lead to induction of adaptive immune responses after treatment with TrisomAb.
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