A progressively growing tumor has been shown to require several sequential steps of mutation and selection. First, there is a normal (N) yields transformed (A) mutation revealed in vitro by anchorage-independent growth. The A-mutants isolated in the absence of any in vivo surveillance mechanism are now scored for their tumorigenic potential in various manipulated (e.g., ATxFL) and normal mice. This permits a classification of an A-line (defined in vitro) into three groups: O (non-tumorigenic), I (tumorigenic in ATxFL only), C (tumorigenic in ATxFL and normal mice). In the case of I-lines there is no doubt that the manipulation, ATxFL, has impaired surveillance. The proposal is to characterize I-lines and their mutation to C. The C-mutants will be isolated from I by imposing both in vivo as well as in vitro single step selection using various immune (e.g., Tk-activity, ADCC, C'-lysis, etc.) and non-immune (e.g., NK-activity) effector mechanisms. The properties of the I and C variants will be analyzed to determine: (a) their cross-resistance patterns; (b) their ability to grow alone or in combinations as progressive tumors; (c) the immune-response they induce; (d) the rate at which they vary to resistance; (e) the number of different tumor-associated antigens they express; (f) whether the determinants recognized by the humoral and cell-mediated effector systems are the same; (g) what proportion of transformants (A) isolated by altered behavior in tissue culture are O, I, and C variants; and (h) whether the major histocompatibility complex determines or contributes to the recognition of the tumor-associated determinants. A comparison of the resistance to immune effector attack and of the class of response induced by various I-lines will enable us to make general and predictive rules about tumor escape patterns. One particularly important comparison will be between the in vivo and the in vitro immunoselected derivatives. This will tell us which are the major and which the minor routes of escape and whether all routes involve the immune system. Those which do not, will lead us to study non-immune surveillance.