THE NKG2D LIGAND MICA FOSTERS TUMOR IMMUNESURVEILLANCE OF NK CELLS IN A BREAST CARCINOMA MODEL THROUGH INHIBITION OF MDSC EXPANSION RESULTING IN DIMINISHED METASTASES

MARÍA CECILIA SANTILLI; MARÍA VICTORIA REGGE; MARIANA GANTOV; ADRIÁN FRIEDRICH; MARÍA NATALIA RUBINSZTAIN; BELÉN CANDELA LOZADA MONTANARI; MARÍA SOFÍA AMARILLA; ALDANA TROTTA; MERCEDES BEATRIZ FUERTES; CAROLINA INÉS DOMAICA; NORBERTO WALTER ZWIRNER

Congreso; Reunion anual de la SAI; 2023

The MHC class I chain-related protein A (MICA) is as a cell surface molecule recognized by theNKG2D receptor found on the surface of natural killer (NK), γδ T, and CD8 + T cells. Beingpredominantly expressed by tumor cells of diverse phenotypes, MICA has emerged as a potentialtherapeutic target in immuno-oncology. To investigate the impact of MICA expression on myeloidsuppressor cells (MDSC), female BALB/c mice were challenged with MICA-expressing (4T1-MICA)or control 4T1 murine triple-negative breast carcinoma cells. First, we observed that subcutaneousinjection of 30,000 cells led to the development of aggressively growing tumors, lung metastases,and splenomegaly only in mice challenged with 4T1 cells but not in mice challenged with 4T1-MICA cells. To achieve sustained tumor growth, it was necessary to challenge mice with 250,0004T1-MICA cells. Both 4T1 and 4T1-MICA tumors exhibited similar growth rates until day 7. Then,4T1-MICA displayed a regression and resumed to grow only after day 15, which suggests thatMICA expression facilitated tumor growth control. Notably, 4T1-MICA tumor-bearing mice did notexhibit the splenomegaly characteristic of 4T1 tumor-bearing mice (spleen weight/mean±SEM4T1: 513.2±126.5 mg; 4T1-MICA:125.2±20.8 mg; p<0.05). This reduced splenomegaly in 4T1tumor-bearing mice was accompanied by a diminished content of granulocytic MDSC (frequencyof Ly6G + Ly6C - CD11b + cells/mean±SEM 4T1: 28.7±3.3%; 4T1-MICA: 10.1±3.0%; p<0.01), andmonocytic MDSC (frequency of Ly6C + Ly6G - CD11b + cells/mean±SEM 4T1: 3.6±0.7%; 4T1-MICA:0.9±0.2%; p<0.01). Furthermore, ex vivo analysis demonstrated that splenic NK cells from 4T1tumor-bearing mice exhibited a lower percentage of degranulation in response to stimulation withYAC-1 cells than splenic NK cells from 4T1-MICA tumor-bearing mice (frequency of CD107a + NKcells relative to unstimulated cells/mean± SEM 4T1 1.0±0.1%; 4T1-MICA 1.5±0.1%; p<0.01). Also,splenic NK cells from 4T1 tumor-bearing mice exhibited a lower frequency of IFN- γ -producing NKcells in response to stimulation with cytokines than splenic NK cells from 4T1-MICA tumor-bearingmice (frequency of IFNγ + NK cells relative to unstimulated cells/mean± SEM 1.3±0.1%; 4T1-MICA:2.8±0.6%; p<0.05). This less immunosuppressive environment in spleens of 4T1-MICA tumor-bearing mice resulted in a significantly lower lung metastases (number of macrometastases inlung/ mean±SEM 4T1:12.7±6.9%, 4T1-MICA: 0.2±0.2%; p<0.01). We conclude that MICAexpression in the 4T1 model enhances tumor immunosurveillance by preventing the expansion ofsplenic MDSC and increasing the effector activity of NK cells.