The MICA-NKG2D axis and the validation of a novel target in immuno-oncology

ZWIRNER, NORBERTO WALTER

Mar del Plata

Simposio; 70ª Reunión Anual de la Sociedad Argentina de Inmunología y 3rd French-Argentine Immunology Congress (FAIC); 2022

Sociedad Argentina de Inmunología

NK cells are currently at the forefront in immuno-oncology. To exploit their antitumor potential, several monoclonal antibodies (mAb) that target immune checkpoints on NK cells are under investigation, while other mAb that promote ADCC (antibody-dependent cell-mediated cytotoxicity) constitute the current standard of care for some cancer patients. NK cells express NKG2D, an activating receptor that promotes NK cell effector functions and tumor elimination through recognition of several ligands (NKG2DLs) such as MICA, MICB and the ULBPs 1 to 6. Although NKG2DLs are overexpressed on a wide variety of tumors (making them attractive targets for immunotherapy modalities), tumors can shed NKG2DLs and such soluble forms can subvert the NKG2D-NKG2DL axis and mediate tumor-immune escape. To validate MICA as a novel target in immuno-oncology, we explored whether deliberately induced anti-MICA (Ab) elicited by vaccination with a chimeric protein harboring the ectodomain of MICA can promote the restoration of antitumor immunity. Indeed, such Ab delayed the growth of MICA-expressing tumors, and their mechanism of action involved the induction of ADCC by NK cells and scavenging of sMICA, which resulted in a remodeling of the tumor microenvironment. Also, studies in cell renal cell carcinoma patients demonstrated that MICA is overexpressed in this type of tumor and associated with diminished overall survival. Expression of MICA was detected on tumor cells, including cancer stem cells, and tumor-infiltrating leukocytes, but not on peripheral blood lymphoid cells. Also, tumor-infiltrating NK cells exhibited impaired effector functions, features of exhaustion and an altered metabolic fitness. Thus, expression in primary tumor cells and druggability with Ab validate MICA as a leading-edge target for innovative immunotherapy strategies based on the use of anti-MICA mAb that may reinstate antitumor immunity unleashing NK cell effector functions to treat a wide range cancer patients.