ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY MEDIATED BY NATURAL KILLER CELLS IN TUMOR IMMUNOTHERAPY WITH THERAPEUTIC ANTIBODIES

LEVY, ESTRELLA MARIEL

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

Breast cancer (BC) is one of the leading causes of death worldwide and usually remains incurable in advanced stages. Generally, BC is not considered an inflammatory tumor although triple-negative BC (TNBC) and HER2+ tumors are more immunogenic than the most common luminal A-like subtype. Two of the most important targeted cancer therapies today are based on monoclonalantibodies (mAbs). Among the mAbs directed to tumor antigens, cetuximab targets the epidermal growth factor receptor (EGFR) and trastuzumab the HER2. Whereas avelumab that targets PD-L1 belongs to a type of mAbs that block immune checkpoints. Since all these mAbs areIgG1, they could potentially mediate Ab-dependent cellular cytotoxicity (ADCC) against tumor cells. As EGFR and PD-L1 are overexpressed in TNBC, they represent potential therapeutic targets for certain subsets of patients. While for HER2+ tumors, trastuzumab together with pertuzumab constitute already a therapeutic reality. In recent years, our group has focused on the role ofNK cells in therapy with these mAbs directed to TNBC or HER2+ cells. We determined that avelumab significantly improved NK cell-mediated cytotoxicity against TNBC cells expressing high levels of PD-L1. Furthermore, IL-2 and IL-15 stimulation of NK cells enhanced Ab-dependent cytokine release and degranulation along with increased lytic activity against tumor cells. We alsoexamined the interaction between NK cells and dendritic cells (DCs) promoted by the anti-EGFR mAb. We found that opsonization of TNBC cells by cetuximab increased IFN-γ/TNF-α production and ADCC mediated by NK cells. Therefore, activated NK cells stimulated tumor material uptake and maturation of DCs. Furthermore, the addition of IL-15 increased both NK cell activation andDCs maturation. Nowadays, we are analyzing adaptive NK cells (aNK cells) that expand after human cytomegalovirus (HCMV) infection. aNK cells exhibit interesting properties that could be exploited for therapy with mAbs, including their longevity and their enhanced functionalactivity and proliferation in response to stimulation by CD16. We found that a high proportion of BC patients were HCMV+ and most of them had an aNK cell subpopulation. aNK cells produced more IFN-γ than their conventional (cNK) counterparts, against trastuzumab/pertuzumab-opsonized HER2+ cells. Besides, in a group of patients treated with chemotherapy, trastuzumab andpertuzumab, aNK cells retained greater IFN-γ than cNK cells after treatment. Our findings may have implications for therapy with mAbs directed to breast tumors. For this reason, our group continues working on understanding how NK cells could contribute to these treatments’ efficacy.