REGULATION OF LOCAL HOST-MEDIATED ANTITUMOR MECHANISMS BY CYTOKINES -DIRECT AND INDIRECT EFFECTS ON LEUKOCYTE RECRUITMENT AND ANGIOGENESIS

The regulation of tumor growth by cytokine-induced alterations in host effector cell recruitment and activation is intimately associated wit h leukocyte adhesion and angiogenic modulation. In the present study, we have developed a novel tumor model to investigate this complex seri es of events in response to cytokine administration. Gelatin sponges c ontaining recombinant human basic fibroblast growth factor (rhFGFb) an d B16F10 melanoma cells were implanted onto the serosal surface of the left lateral hepatic lobe in syngeneic C57BL/6 mice. The tumor model was characterized by progressive tumor growth initially localized with in the sponge and the subsequent development of peritoneal carcinomato sis. Microscopic examination of the sponge matrix revealed well develo ped tumor-associated vascular structures and areas of endothelial cell activation as evidenced by leukocyte margination. Treatment of mice 3 days after sponge implantation with a therapeutic regimen consisting of pulse recombinant human interleukin-2 (rhIL-2) combined with recomb inant murine interleukin-12 (rmIL-12) resulted in a marked hepatic mon onuclear infiltrate and inhibition of tumor growth. In contrast to the control group, sponges from mice treated with rhIL-2/rmIL-12 demonstr ated an overall lack of cellularity and vascular structure. The regime n of rhIL-2 in combination with rmIL-12 was equally effective against gelatin sponge implants of rhFGFb/B16F10 melanoma in SCID mice treated with anti-asialo-GM1 in the absence of a mononuclear infiltration, su ggesting that T, B, and/or NK cells were not the principal mediators o f the anti-tumor response in this tumor model. The absence of vascular ity within the sponge after treatment suggests that a potential mechan ism of rhIL-2/rmIL-12 anti-tumor activity is the inhibition of neovasc ular growth associated with the establishment of tumor lesions. This p otential mechanism could be dissociated from the known activities of t hese two cytokines to induce the recruitment and activation of host ef fector cells. Moreover, this model provides a unique opportunity to st udy the cellular and molecular mechanism(s) underlying both tumor angi ogenesis and leukocyte recruitment to metastatic lesions.