We have demonstrated by histology, immunohistology and proliferation responses to phytomitogens, alloantigens and lymphokines, that lymph nodes near to primary or metastatic malignant melanoma are less reactive than those located further from tumor. Poorly reactive nodes near to tumor are also those which show the earliest evidence of metastases, single cell penetration by tumor cells. Reactive nodes located further from tumor do not show single cell penetration. While the coexistence of poor reactivity and early metastatic disease in nodes near to tumor could be fortuitous it may be evidence that tumors create the conditions necessary for metastatic spread by producing materials (prostaglandins, gangliosides high concentrations of tumor antigens) which suppress lymph node functions. We will investigate the specific interaction of tumor cells and lymph node cells (LNC) by comparing the anti-tumor effector capacity of LNC from nodes near to tumor and those further away. In these studies we will assess the tumoricidal activity of nodal lymphocytes stimulated by Interleukin-2 (IL-2), of lymphocytes stimulated by mixed lymphocytes tumor cell coculture and of lymph nodal macrophages. We will also examine the survival of autologous melanoma cells cultured in the presence of lymph node cells from nodes located at different distances from tumor. Studies of the mechanism of reduced reactivity in nodes near to tumor suggest that the effect is due to an excess of Con A inducable suppressor cells in the nodes near tumor and that tumor-derived materials such as prostaglandins and certain gangliosides may be active in reducing node activity. Such materials can certainly reduce LNC activity (response to IL-2) in vitro. We will therefore assess whether the reduced activity of LNC from tumor-proximate nodes can be increased by materials which inhibit cytotoxic cells (e.g., 4-OH cyclophosphamide) or by prostaglandin inhibitors (e.g., Indomethacin). We will also examine the effect of biological response modifiers, such as Gamma-interferon in reversing reduced LNC function. These in vitro studies will identify materials worthy of consideration for evaluation in vivo in attempts to prevent or abort these early critical steps in the metastatic process. We believe that the development of techniques to prevent metastases represent the most logical approach to reducing cancer mortality that is attainable in the short term.
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