ANTI-TRANSFORMING GROWTH-FACTOR (TGF)-BETA ANTIBODIES INHIBIT BREAST-CANCER CELL TUMORIGENICITY AND INCREASE MOUSE SPLEEN NATURAL-KILLER-CELL ACTIVITY - IMPLICATIONS FOR A POSSIBLE ROLE OF TUMOR-CELL HOST TGF-BETA INTERACTIONS IN HUMAN BREAST-CANCER PROGRESSION

TGF-beta effects on angiogenesis, stroma formation, and immune functio n suggest its possible involvement in tumor progression. This hypothes is was tested using the 2G7 IgG2b, which neutralizes TGF-beta1, -beta2 , and -beta3, and the MDA-231 human breast cancer cell line. Inoculati on of these cells in athymic mice decreases mouse spleen natural kille r (NK) cell activity. Intraperitoneal injections of 2G7 starting 1 d a fter intraperitoneal inoculation of tumor cells suppressed intraabdomi nal tumor and lung metastases, whereas the nonneutralizing anti-TGF-be ta 12H5 IgG2a had no effect. 2G7 transiently inhibited growth of estab lished MDA-231 subcutaneous tumors. Histologically, both 2G7-treated a nd control tumors were identical. Intraperitoneal administration of 2G 7 resulted in a marked increase in mouse spleen NK cell activity. 2G7 did not inhibit MDA-231 primary tumor or metastases formation, nor did it stimulate NK cell-mediated cytotoxicity in beige NK-deficient nude mice. Finally, serum-free conditioned medium from MDA-231 cells inhib ited the NK cell activity of human blood lymphocytes. This inhibition was blocked by the neutralizing anti-TGF-beta 2G7 antibody but not by a nonspecific IgG2. These data support a possible role for tumor cell TGF-beta in the progression of mammary carcinomas by suppressing host immune surveillance.