STRATEGIES TO ENHANCE NATURAL KILLER ACTIVITY IN CANCER THERAPY.

LEVY, ESTRELLA MARIEL

Conferencia; LXVI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2022

Natural Killer (NK) cells are central components of innateimmunity. Because of their potential to induce direct cellularcytotoxicity without prior sensitization and releaseimmunostimulatory cytokines like IFN-γ, NK cells havebeen 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 ourgroup, we observed altered phenotype and functionalityin peripheral and tumor-associated NK cells from patientswith colorectal (CRC) and breast cancer (BC) (1-4).NK cells are feasible targets of stimulation to participate inimmunotherapeutic approaches like antibody (Ab)-basedstrategies. In several medical scenarios, NK cells can beactivated by tumor-associated antigen-specific therapeuticAbs via CD16a-mediated ADCC effects. Cetuximab isan anti-EGFR chimeric mAb. We determined that alteredNK cells in CRC patients can be activated by Cetuximabplus Il-2 or Il-15 (4). Also, we demonstrated that Cetuximabtriggers ADCC against Triple-negative BC (TNBC)cells (5). Moreover, we determined that Cetuximab opsonizationof TNBC cells increased a cross-talk betweenNK and dendritic cells (6).Nowadays, several mAbs are being studied to block thePD-1/PD-L1 axis in different tumors; preliminary datafrom clinical trials presented promising results for patientswith advanced-stage/metastatic TNBC. Unlike otheranti-PD-L1 mAbs, Avelumab was designed as IgG1to trigger ADCC against tumor cells. We demonstratedthat Avelumab significantly enhanced NK-cell mediatedcytotoxicity against TNBC cells and that tumor cellsexpressing higher levels of PD-L1 were more sensitiveto Avelumab-mediated ADCC. Our study suggests thatAvelumab-mediated ADCC, independently of the blockadeof the PD-1/PD-L1 pathway, could be a valuablemechanism for tumor cell elimination in TNBC (7).Emerging evidence suggests that a subset of NK cellshave adaptive immune features, including memory-likeproperties, 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-γproduction compared to conventional NK cells via theanti-HER Ab (Trastuzumab)-mediated ADCC (unpublisheddata). Our results encourage studying NKa cellsas a potential candidate for predicting Ab-based therapyoutcomes in HER2+ BC.