Producción CyT
Libro de Resúmenes del Congreso - The NKG2D ligand MICA fosters tumor immunesurveillance of NK cells in a breast carcinoma model through inhibition of MDSC expansion resulting in diminished metastases.
Congreso
Autoría:
Santilli, María Cecilia ; Regge, María Victoria ; Gantov, Mariana ; Friedrich, Adrián David ; Rubinsztain, Maria Natalia ; Lozada Montanari, Belen candela ; Amarilla, Maria Sofía ; Trotta, Aldana ; FUERTES, MERCEDES BEATRIZ ; Domaica, Carolina Inés ; Zwirner, Norberto WalterFecha:
2023Editorial y Lugar de Edición:
Nueva Editorial UniversitariaISSN:
978-987-733-386-2Resumen *
The MHC class I chain-related protein A (MICA) is as a cell surface molecule recognized by the NKG2D receptor found on the surface of natural killer (NK), γδ T, and CD8+ T cells. Being predominantly expressed by tumor cells of diverse phenotypes, MICA has emerged as a potential therapeutic target in immuno-oncology. To investigate the impact of MICA expression on myeloid suppressor 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 subcutaneous injection 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 250,000 4T1-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 that MICA expression facilitated tumor growth control. Notably, 4T1-MICA tumor-bearing mice did not exhibit the splenomegaly characteristic of 4T1 tumor-bearing mice (spleen weight/mean±SEM 4T1: 513.2±126.5 mg; 4T1-MICA:125.2±20.8 mg; p<0.05). This reduced splenomegaly in 4T1 tumor-bearing mice was accompanied by a diminished content of granulocytic MDSC (frequency of Ly6G+Ly6C-CD11b+ cells/mean±SEM 4T1: 28.7±3.3%; 4T1-MICA: 10.1±3.0%; p<0.01), and monocytic 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 4T1 tumor-bearing mice exhibited a lower percentage of degranulation in response to stimulation with YAC-1 cells than splenic NK cells from 4T1-MICA tumor-bearing mice (frequency of CD107a+ NK cells 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 NK cells in response to stimulation with cytokines than splenic NK cells from 4T1-MICA tumor-bearing mice (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 in lung/ mean±SEM 4T1:12.7±6.9%, 4T1-MICA: 0.2±0.2%; p<0.01). We conclude that MICA expression in the 4T1 model enhances tumor immunosurveillance by preventing the expansion of splenic MDSC and increasing the effector activity of NK cells Información suministrada por el agente en SIGEVAPalabras Clave
BREAST CARCINOMANATURAL KILLERMICANKG2D