Poster Presentation 36th Lorne Cancer Conference 2024

CD155 plays a dominant role in modulating NK cell activation (#147)

Tania Allin Vargas Pavia 1 , Philippa Saunders 1 , Clare Oates 1 , Andrew Brooks 1
  1. Department of Microbiology and Immunology , The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Victoria, Melbourne, Australia

Overexpression of nectin and nectin-like molecules has been associated with poor prognoses in several cancer types. These molecules form ligands for immune receptors of the Poliovirus Receptor (PVR) co-signaling network expressed on Natural Killer (NK) cells. However, there are still gaps in our knowledge of how this network modulates NK cell function. To better define the outcomes of these interactions, 293T cells were modified in their expression of CD112 and CD155, and assessed for their capacity to elicit chemokine, cytokine, and degranulation responses in primary NK cells. While CCL4 and CD107a expression were largely unaffected by ligand modulation, IFN-ү responses showed notable differences. Loss of CD112 slightly increased cytokine production while the absence of CD155 did not impact NK cell function. However, overexpression of CD155 decreased IFN-ү production regardless of the presence of CD112. To evaluate which receptors were responsible for these effects, CD155 was mutated at residues that differentially contact activating DNAM-1 or inhibitory CD96/TIGIT receptors. Modest differences in IFN-ү production were only observed for mutants involved in DNAM-1 recognition, implicating DNAM-1 as a regulator of NK cell responses towards CD155-expressing targets. Several mutations in CD155 are also associated with poor prognosis in different cancer types, however whether they impact DNAM-1 or inhibitory receptor engagement is unknown. Consequently, we generated a panel of cells expressing such CD155 mutants and again found they modulated IFN-γ production by NK cells, with a more striking reduction of IFN-ү seen with high levels of expression of CD155. Together, this data shows that differences in CD155 expression modulates the production of cytokines by NK cells and that higher levels of CD155 expression inhibits NK cells. Understanding the extent to which elevated CD155 expression impacts competition between receptors or drives divergent patterns of signaling across the network may better direct PVR-targeted strategies for cancer immunotherapy.