Proteolytic processing of human
plasminogen generates potent antiangiogenic
peptides such as
angiostatin. The
plasminogen kringle 5 (K5) domain, which is distinct from
angiostatin, possesses potent antiangiogenic properties on its own, which can be exploited in
cancer therapy. It has been recently observed that
antiangiogenic agents promote leukocyte-vessel wall interaction as part of their antitumor effect. Although we have previously shown that K5 suppresses
cancer growth in
tumor xenograft models, its modulation of
inflammation in experimental mice with intact immune systems is unknown. To determine whether K5 possesses immune proinflammatory properties, we investigated the effects of K5 in an immune competent model of
breast cancer and observed that
tumor rejection is substantially reduced in nonobese diabetic/severe combined immunodeficient and BALB/c nude when compared with wild-type BALB/c mice, suggesting an important role for T-lymphoid cells in the antitumor effect of K5.
Tumor explant analysis shows that K5 enhances
tumor recruitment of CD3(+) lymphoid cells, in particular, the NKT phenotype. We also observed a significant decrease in
tumor-associated microvessel length and density consistent with antiangiogenic activity. Histologic analysis of K5
tumors also revealed a robust neutrophilic infiltrate, which may be explained by the neutrophil chemotactic activity of K5 as well as its ability to promote CD64 up-regulation within the CD11b(+) adhesive neutrophil population. In sum, our findings confirm that the K5
protein acts as a potent
angiostatic agent and possesses a novel proinflammatory role via its ability to recruit
tumor-associated neutrophils and NKT lymphocytes, leading to a potent antitumor response.