The cutaneous tumors derived by exposure to ultraviolet light (UV) are antigenic, and normally rejected when transplanted in syngeneic, immune competent recipients. The tumors escape immunological rejection in the original hosts because of a UV-mediated modulation of the immune system. Topical exposure to the tumor promoter 12-0-tetradecanoylphorbol-13- acetate (TPA) evokes an immunomodulation in SSIN (inbred SENCAR) mice that is similar to that caused by UV, which may be germane to the mechanism whereby TPA facilitates the development of initiated cells into tumors. Specifically, we have recently found that the primary papillomas generated in SSIN mice as a consequence of 7, 12-dimethylbenz[a] anthracene (DMBA) initiation / TPA promotion grow when s.c. transplanted into athymic nude mice, but regress and disappear when transplanted into naive, immune competent syngeneic or allogeneic hosts. Based upon these observations, we hypothesize that the papillomas generated in DMBA initiation / TPA-promotion protocols are antigenic, but escape rejection due to a promoter-mediated modulation of the immune system. In order to examine this hypothesis we propose: 1) to generate cell lines from skin papillomas harvested from initiated / TPA-promoted SSIN mice; 2) evaluate the in vivo growth / rejection of these cell lines and primary papillomas when s.c. transplanted into athymic nude mice, immunosuppressed syngeneic mice, and immune competent syngeneic mice; 3) determine if treatment of naive mice with initiating doses of DMBA, and / or promoting doses of TPA and other chemical promoters can suppress the rejection of s.c. transplanted papilloma cell lines or primary tumors; and 4) determine by adoptive transfer studies if the lack of immune rejection in initiated / promoted mice is mediated by an immune suppressor population. If so, the phenotype of the suppressor population will be characterized. 5) We will also determine the effects of topically applied TPA on antigen presentation and the activation and / or induction of anergy in CD4+ helper T cell subsets (e.g., Th1 and Th2 T cells), and 6) characterize the effects of DMBA and chemical promoters on the effector cells (natural killer cells, cytotoxic T cells) that participate in tumor rejection. 7) In order to better approximate the environment of epidermal tumor growth, we will use epidermal chambers to assess the effects of in vivo topical promoter treatment on the growth/rejection of grafted papilloma cell lines in the epidermis. The proposed research addresses a topic that has been ignored by investigators in the tumor promotion field, and explores a new and unique mechanism that might be germane to the mechanism whereby chemical promoters facilitate the development of initiated cells into tumors.
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