Adaptive Natural Killer (NKa) Cells Facilitate Effector Functions of Trastuzumab in Breast Cancer (BC)

MARIA BELEN BORDIGNON; AYELÉN IVANA PESCE VIGLIETTI; ESTEFANIA PAULA JULIÁ; PABLO MANDÓ; LUCIANA SABATINI; JOSE MORDOH; LEONARDO FAINBOIM; ESTRELLA MARIEL LEVY

Congreso; Reunión Anula de Sociedades de Biociencias; 2020

NK cells have been regarded as the primary effectors of innate immunity, but emergingevidence suggests that a subset of NK cells has adaptive immune features, including memory-like properties, such as long-term persistence, robust preferential expansion in response toviral infection, and enhanced antibody-dependent effector functions. This subset of NK cells ischaracterized by a lack of FcƐRIγ expression and/or high expression of NKG2C.Objective: To identify in BC patients NK-cell subpopulations and to characterize NK-cell subsetsthat support the robust anti-BC activity of trastuzumab (TRZ) via ADCC.With this aim we analyzed in their PBMCs the cellular composition of the NK-cell subsets; wedefined adaptive (NKa) and conventional NK (NKc) cells as FcRγ- and FcRγ+, respectively.We analyzed immunophenotypes of NKc and NKa cells in PBMCs samples derived from ourcohort of 60 BC patients and 32 healthy donors (HD), both with 85% human cytomegalovirus(HCMV) seropositivity. We characterized the differential expression pattern of NK-cellinhibitory and activating receptors. Unlike NKc cells, NKa cells expressed significantly higherlevels of NKG2C (<0,0001) and CD85j (<0,0001), and lower levels of NKp30 (<0,0001), CD161(<0,0001) and CD16 (p<001), (paired t-tests), which is consistent with previous observations inHD.To understand the functional consequences of these findings we then, compared theproduction of IFNγ by NKc and NKa cells from BC patients and HD. We cultured PBMC withSKBR3 cells (HER2+) ± TRZ for 6 hours. When treated with TRZ, NKa cells from BC patients andHD exhibited strong IFNγ production compared with NKc cells (p<0.01, paired t-test).Conclusions: NKa cells have different immunophenotypic characteristics than NKc cells in BC.Ex vivo treatment of PBMC with TRZ, reveals superior effector functions of NKa cells. Ourresults highlight the NKa cells as a potential candidate for predicting Ab-based therapyoutcomes in BC-HER2+.