The objective is to characterize the immune reactions involved in the rejection of contact-noninhibited cells in the early stage of tumorigenesis, and to determine how cells in the late stages of tumorigenesis escape immune rejection. This will be accomplished by first isolating contact-nonihibited cell lines in vitro following the exposure of a cloned nontransformed cell line (i.e., an N-line) to a chemical carcinogen [benzo(a)pyrene]. The contact-noninhibited cell lines will then be tested for their tumorigenicity in syngeneic normal and immune-depressed (nude) mice. Those contact-noninhibited cell lines that represent cells in an early stage of tumorigenesis (i.e., I-lines) will be identified by their ability to grow as tumors in nude mice, but not in normal mice. Cell lines representing late stages of tumorigenesis (i.e., C-lines) will be isolated from the I-lines by in vivo selection for cells that are tumorigenic in normal as well as nude mice. The isolation of sequentially derived cell lines representing a progression in tumorigenicity of the type N to I to C permits an immunological analysis of the events associated with tumorigenicity and sensitivity to immune rejection (N to I) to be conducted independent of the analysis of the events associated with the escape from immune rejection (I to C). Because the I-lines will be isolated in the absence of immune selection, the analysis of the immune response they induce in normal mice can be used to identify antigens expressed by the I-lines and the type of immune response that mediates their rejection. Because the C-lines will be derived from I-lines by selecting, in vivo, for cells that are tumorigenic in normal mice, the analysis of their ability to induce an immune response and their sensitivity to immune effector mechanisms will reveal how tumors escape immune rejection. Only by analyzing the pathway by which nontransformed cells become tumorigenic in normal mice can we hope to understand the involvement of the immune system in this pathway. The proposed analysis will provide some of the much needed basic information on the role of the immune system in tumor rejection and in so doing could provide a basis for extrapolating from the events in volved in tumor progression in this animal model system to tumor progression in man.
| Vanderslice, W E; Collins, J L (1991) Differences in the tumor necrosis factor-alpha-mediated lysis by fixed natural cytotoxic cells and fixed cytotoxic macrophages. J Immunol 146:156-61 |
