TY - JOUR
T1 - The FcγRIIIA (CD16) L48-H/R polymorphism enhances NK cell-mediated antibody-dependent cellular cytotoxicity by promoting serial killing
AU - Maskalenko, Nicholas A
AU - Zahroun, Sam
AU - Tsygankova, Oxana
AU - Anikeeva, Nadia
AU - Sykulev, Yuri
AU - Campbell, Kerry S
PY - 2024/11/12
Y1 - 2024/11/12
N2 - Many tumor-specific monoclonal antibody therapies stimulate antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells through FcγRIIIa (CD16). The efficacy of these ADCC-based immunotherapies is potentiated in patients with the common CD16 polymorphic variant F158-V that increases the binding affinity between the receptor and the IgG Fc domain. However, other CD16 variants are less well characterized. Here, we report that CD16 L48-H and L48-R variants both significantly enhance in vitro ADCC responses in primary NK cells and NK-92 cells. During ADCC responses, NK cells expressing CD16 48-H killed and disengaged from target cells faster than those expressing CD16 48-L, resulting in improved serial killing of tumor cells. We found that CD16 48-H also formed an immunological synapse with a more compact interface, as well as more robust intracellular calcium signaling and quicker polarization of cytolytic vesicles. The ADCC response observed occurs due to increased cytolytic signaling and target cell disengagement, which drives NK cell-mediated serial killing of tumor cells. The L48-H/R polymorphism has potential to benefit patient responses to cancer antibody therapies and may also potentiate anti-tumor ADCC responses if incorporated into adoptive NK cell therapeutic platforms.
AB - Many tumor-specific monoclonal antibody therapies stimulate antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells through FcγRIIIa (CD16). The efficacy of these ADCC-based immunotherapies is potentiated in patients with the common CD16 polymorphic variant F158-V that increases the binding affinity between the receptor and the IgG Fc domain. However, other CD16 variants are less well characterized. Here, we report that CD16 L48-H and L48-R variants both significantly enhance in vitro ADCC responses in primary NK cells and NK-92 cells. During ADCC responses, NK cells expressing CD16 48-H killed and disengaged from target cells faster than those expressing CD16 48-L, resulting in improved serial killing of tumor cells. We found that CD16 48-H also formed an immunological synapse with a more compact interface, as well as more robust intracellular calcium signaling and quicker polarization of cytolytic vesicles. The ADCC response observed occurs due to increased cytolytic signaling and target cell disengagement, which drives NK cell-mediated serial killing of tumor cells. The L48-H/R polymorphism has potential to benefit patient responses to cancer antibody therapies and may also potentiate anti-tumor ADCC responses if incorporated into adoptive NK cell therapeutic platforms.
U2 - 10.1158/2326-6066.CIR-24-0384
DO - 10.1158/2326-6066.CIR-24-0384
M3 - Article
C2 - 39666369
SN - 2326-6066
JO - Cancer Immunology Research
JF - Cancer Immunology Research
ER -