Poster Presentation 18th International Symposium on Dendritic Cells 2026

Deletion of Phosphoinositide 3-kinase-γ (PI3Kγ) enhances conventional Dendritic Cell Cross-Presentation of Immune Complexes (#120)

Kenneth M Adusei 1 2 3 , Benjamin M. Murter 1 3 , Alex J. Lee 1 3 4 , Mei Fong Ng 1 3 , Neha Sane 1 3 , Samhita Vitta 1 3 5 , Judith A. Varner 6 , Jelani C. Zarif 1 3
  1. Bloomberg~Kimmel Institute for Cancer Immunotherapy Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  2. Biomedical Engineering, Johns Hopkins University School of Medicine , Baltimore, Maryland, USA
  3. Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer, Baltimore, Maryland, USA
  4. Immunology, Johns Hopkins University School of Medicine , Baltimore, Maryland, USA
  5. Pathobiology, Johns Hopkins University School of Medicine , Baltimore, Maryland, USA
  6. University of California San Diego, Moores Cancer Center , San Diego, California, USA

Phosphoinositide 3-kinase-γ (PI3Kγ) is a lipid kinase mainly expressed in myeloid cells such as dendritic cells (DCs) and macrophages. It has been shown to promote immunosuppressive macrophage cell polarization and immune-mediated tumor growth in multiple pre-clinical murine cancer models. Consequently, targeting PI3Kγ in these models has successfully reduced tumor growth through myeloid-mediated activation of T cells. While PI3Kγ has been well characterized in other immune cells, little is known on how PI3Kγ regulates DCs. To investigate potential roles of PI3Kγ in DC function, we characterized DCs from wildtype (WT) and PI3Kγ knockout (p110γ-/-) mice. Flow cytometry revealed that deletion of PI3Kγ was detrimental to type 1 and 2 conventional DC (cDC1 and cDC2) establishment in the spleen as they were found in lower frequencies compared to WT mice. Interestingly, p110γ-/- cDC1s and cDC2s had substantial upregulation of FC gamma receptor IV (CD16.2), a known mediator of cross-presentation of immune complexes (ICs) by cDCs. As such, we hypothesized that this increase in CD16.2 expression on p110γ-/- cDCs would lead to more efficient cross-presentation of ICs compared to WT cDCs. Intravenous injection of immune complexed ovalbumin bound to fluorescein isothiocyanate (OVA-FITC) showed that p110γ-/- cDCs internalized more immune complexed antigen than their WT counterparts. Additionally, we compared the efficiency of IC cross-presentation between p110γ-/- and WT cDCs using an OVA-OTI adoptive transfer system to observe their ability to drive T cell proliferation. Following the infusion of immune-complexed OVA, OTI T cell proliferation was similar in p110γ-/- and WT mice despite the reduced frequency of cDCs in p110γ-/- mice. These results show that p110γ-/- cDCs more efficiently cross-present immune complexed antigens than WT cDCs. This not only suggests a role for PI3Kγ in cross-presentation but also highlights a therapeutic avenue for PI3Kγ inhibition in combination with anti-tumor antibody immunotherapies.