Microenvironment of the Murine Mammary Carcinoma 4T1: Endogenous IFN-gamma Affects Tumor Phenotype, Growth, and Metastasis

IFN-gamma has a profound influence on growth and metastasis of solid tumors. This is true for the murine mammary carcinoma 4T1 which grows faster and metastasizes much more readily when transplanted into the mammary fatpads of IFN-gamma(-/-) mice. We were interested in determining which infiltrating hematopoietic cells produce IFN-gamma within the 4T1 tumor microenvironment. 4T1 tumors were infiltrated with progressively increasing numbers of F4/80(+)/CD11c(+) myeloid cells, many of which were also Gr-1(+), and Gr-1(+)/CD11b(+) granulocytes. Only small numbers of CD4 T cells, CD8 T cells, NK cells, and gammadelta T cells, the most likely IFN-gamma-producing cells, were seen at any time point. Sensitive intracellular cytokine staining and flow cytometry revealed no tumor-infiltrating hematopoietic cells with detectable levels of intracellular IFN-gamma, although IFN-gamma mRNA transcripts were detected in tumor tissue. However, a progressive increase in the expression of three IFN-gamma-inducible surface membrane proteins (B7-H1, I-A(d), and ICAM-1) on growing 4T1 tumor cells indicated the presence of biologically active IFN-gamma in the tumor microenvironment. Moreover, 4T1 tumor cells from in vitro culture expressed these surface molecules 48 h after intratumoral injection into mature tumors. These data suggest that very low amounts of endogenous IFN-gamma elaborated by infiltrating hematopoietic cells within the microenvironment of a solid tumor can achieve biologically active concentrations and affect tumor phenotype, growth, and metastasis.