The liver is the most common organ site for primary or metastatic cancers, responsible for over one million deaths a year. For either primary or metastatic tumors, liver resection represents the only curative treatment to date. Even after what is planned as curative resections, however, tumor recurrence occurs in the majority of patients, and often in a short period of time. The most likely place for recurrence is in the residual liver, indicating that undetected microscopic disease at the time of liver resection is responsible for such failures. There is evidence that immunosuppression associated with liver resection, characterized by local macrophage dysfunction as well as lymphocyte dysfunction may allow accelerated growth of microscopic residual tumors. The current proposal will examine the cellular immune defects associated with liver resection, by dissecting the relative contributions of macrophage and lymphocyte tumoricidal function to local liver tumor surveillance. These studies will seek to establish a causative relationship between macrophage or lymphocyte dysfunction and accelerated tumor growth after hepatectomy by attempting to reverse the associated cellular immune dysfunction. Gamma-IFN or muramyl-tripeptide (MTP-PE) will be administered systemically with the aim of specifically stimulating macrophage function. Local liver delivery of cytokines [interleukin (IL)-2, IL-12, or granulocyte macrophage-colony stimulating factor (GM-CSF)] by herpes viral vector mediated gene transfer will target lymphocyte immune function. The potential for either or both of these strategies to reverse the cellular immunosuppression associated with hepatectomy and attenuate the effects liver resections have on promoting growth of local tumor will be examined in a clinically relevant model not only to scrutinize the biologic basis of tumor growth within the liver but also to consider therapeutic strategies. In addition to examining the effect of such immune therapies on tumor growth, we will determine if such therapy may be detrimental to liver regeneration. Thus, the specific goals of this application are to further characterize the cellular immune changes associated with hepatectomy, to determine if manipulation of these immune changes may alter growth of microscopic residual tumor, with the hope that a therapeutic strategy directed at stimulation of cellular tumor surveillance may provide the basis for future therapeutic strategies in man.
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