IMMUNITY AND TUMOR PROGRESSION SYSTEM

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The development of heritable variants with increased malignant growth potential is the hallmark of tumor progression and a major reason for therapeutic failure and lethality of cancer. Murine UV-induced regressor tumors grow in nude but fail to grow in normal mice, thereby demonstrating the remarkable power of the immune system in preventing cancer growth. However, variant cells of repressor tumors can escape strong immunological restraints. The long-term objectives are: to determine the mechanisms by which these variant tumors escape in order to be able to reverse or prevent the process. Diverse parameters, T cells, cytokines and, onco/suppressor genes act through different mechanisms but may all participate in a common pathway that prevents immune rejection or enhances growth of the tumor in the immunocompetent host. A large bank of UV-induced murine tumors was recently derived for these studies. The bank contains closely matched pairs of parental regressor tumors, progressor variants of the same tumor, and autologous non-malignant cells and DNA from the mouse of tumor origin. The specific aims are: (1) To determine whether there is an alteration in the CD8+ T cell response to progressor variants, particularly to those that retain the CTL-defined tumor antigens; (2) To determine whether CD4+ T cells are important for the outgrowth of progressor variants; (3)To determine the role of TGF-beta and TNF in tumor progression and whether these or other cytokines are differentially produced by regressors and progressor variants; (4) To determine whether changes in the expression of certain oncogenes or suppressor genes can cause or prevent tumor escape from T cell-dependent immune destruction; and (5) To search for genes turned on/up or turned off/down during the step of tumor progression that allows progressor tumors to escape normal host immunity.