STRATEGIES TO ENHANCE NATURAL KILLER ACTIVITY IN CANCER THERAPY

LEVY, ESTRELLA MARIEL

Congreso; ANNUAL MEETING OF BIOSCIENCE SOCIETIES 2021; 2023

Natural Killer (NK) cells are central components of innate immunity. Because of their potential to induce direct cellular cytotoxicity without prior sensitization and release immunostimulatory cytokines like IFN-γ, NK cells have been shown to suppress both local tumor growth andmetastasis in animal models. Nevertheless, NK cells display impaired functionality andcapability to infiltrate tumors in cancer patients. In our group, we observed altered phenotype and functionality in peripheral and tumor-associated NK cells from patients with colorectal (CRC) and breast cancer (BC) (1-4).NK cells are feasible targets of stimulation to participate in immunotherapeutic approaches like antibody (Ab)-based strategies. In several medical scenarios, NK cells can be activated by tumor-associated antigen-specific therapeutic Abs via CD16a-mediated ADCC effects. Cetuximab is an anti-EGFR chimeric mAb. We determined that altered NK cells in CRC patients can be activated by Cetuximab plus Il-2 or Il-15 (4). Also, we demonstrated that Cetuximab triggers ADCC against Triple-negative BC (TNBC) cells (5). Moreover, we determined that Cetuximab opsonization of TNBC cells increased a cross-talk between NK and dendritic cells (6).Nowadays, several mAbs are being studied to block the PD-1/PD-L1 axis in different tumors; preliminary data from clinical trials presented promising results for patients with advanced-stage/metastatic TNBC. Unlike other anti-PD-L1 mAbs, Avelumab was designed as IgG1 to trigger ADCC against tumor cells. We demonstrated that Avelumab significantly enhanced NK-cell mediated cytotoxicity against TNBC cells and that tumor cells expressing higher levels of PD-L1 were more sensitive to Avelumab-mediated ADCC. Our study suggests that Avelumab-mediated ADCC, independently of the blockade of the PD-1/PD-L1 pathway, could be a valuable mechanism for tumor cell elimination in TNBC (7).Emerging evidence suggests that a subset of NK cells have adaptive immune features, including memory-like properties, and enhanced Ab-dependent effector functions. Recently we identified and characterized an adaptive (NKa) cell subpopulation in BC patients.NKa cells from BC patients exhibited increased IFN-γ production compared to conventional NK cells via the anti-HER Ab (Trastuzumab)-mediated ADCC (unpublished data). Our results encourage studying NKa cells as a potential candidate for predicting Ab-based therapyoutcomes in HER2+ BC.