Differences in tolerogenic status of NK cells between luminal A type, luminal B type, and triple-negative breast cancer

Alma Starčević, Damir Grebić, Manuela Avirović, Martina Mavrinac, Petra Valković Zujić, Danijela Veljković Vujaklija,  Tamara Gulić

Abstract:

Globally, breast cancer is the main cause of death among female cancer patients. The tumor-infiltrating lymphocytes (TILs) in breast cancer are associated with a more favorable outcome of a disease. Natural killer (NK) cells are important cytotoxic cells involved in tumor immunosurveillance, causing the direct killing of tumor cells. In solid tumors, peripheral NK cells and tumor-infiltrating NK cells display an altered phenotype characterized by reduced cytotoxicity or anergy. The goal of this study was to investigate the NK cells’ phenotype and activation status in order to get into the pathological process of breast cancer subtypes. In our study, the normal tissues and tumoral breast tissue were fixed in formalin, embedded in paraffin, and the phenotypic marker CD56 and proinflammatory cytokine IL-15 were identified by immunohistology. The distribution and expression of receptors repertoire (NKG2A, NKG2C, NKp46, CD94, CD69, and CD107a) were investigated in peripheral NK cells of mononuclear cells by flow cytometry. mRNA of cytolytic mediators was determined by real-time PCR. The frequency of CD56+ and IL-15+ cells were significantly higher in triple-negative breast cancer tissue. The frequency of NK cell activating receptors was decreased in investigated breast cancer subtypes while the inhibitory NKG2A receptor was increased. Decreased percentage of CD69+/CD107a+ in NK cells could indicate lower cellular activation and cytotoxicity. In luminal B breast cancer, the mRNA of cytolytic mediators was upregulated. In conclusion, modulation of activation status in tumor-infiltration NK cells could be involved in the pathogenesis of molecular breast cancer subtypes. This highlights the importance of NK cells as an appropriate target for potent anti-tumor response in the immunosuppressive tumor microenvironment of breast cancer.