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The use of immunosuppressive agents (primarily azathioprine and prednisone) to promote human allograft survival is known to be associated with an enhanced rate of skin cancer development by ultraviolet radiation (UVR). These observations raise the question of whether the immunosuppressive agents are functioning as cocarcinogen or whether they augment UVR-induced tumors by their successive influence on normal tumor-directed immune responses. In this report we have examined the effect of cyclosporine (CsA) on the capacity of murine UVR-induced tumors to grow following their transplantation to syngeneic recipients. We found that transplanted UVR tumors, selected for their inability to grow in normal recipients, were capable of progressive growth following implantation into CsA-treated recipients. This CsA-induced tumor-susceptible state could be reversed by treatment of prospective recipients with the drug cyclophosphamide (CY), supporting the concept that CsA was functioning in vivo by its capacity to promote suppressor cell generation. Further studies established that CsA treatment needed to be given at or near the time of tumor transplantation for susceptibility to occur. Our findings support the possibility that CsA is capable of promoting the survival and progression of UVR-induced skin tumors via its capacity to enhance the dominance of suppressor-cell-controlled immune responses.

Our objective was to determine the relationship between major histocompatibility complex class I molecule expression and the tumorigenic properties of cutaneous neoplasms induced by ultraviolet radiation or chemical carcinogens. All tumors tested were found to express low constitutive levels of MHC class I molecules in vitro as determined by indirect immunofluorescence and flow cytometry. Those tumors capable of growth in UVR-exposed but not in normal recipients (regressors) were found to express enhanced levels of H-2Kk following incubation in the presence of gamma-IFN. In contrast, only one of the tumors that were capable of growth in normal recipients (progressors) exhibited more than moderate enhancement of H-2Kk expression in response to gamma-IFN. Analysis of tumor variants obtained by conversion of a UVR-induced regressor tumor to the progressor phenotype by passage through sublethally gamma-irradiated hosts, or the generation of regressor tumors by mutagen exposure of a benz [A] pyrene (BAP) induced progressor tumor, further supported the direct relationship between tumor immunogenicity in vivo and the capacity to elevate H-2Kk expression in response to gamma-IFN. No correlation existed between H-2Dk expression by the tumors and their transplantation phenotype. Furthermore, we failed to observe MHC class II expression by any of the tumors tested. Finally, the growth rate of a regressor tumor implanted into UVR-exposed hosts was significantly reduced if the tumor was pretreated with gamma-IFN in vitro prior to inoculation. This result suggests that UVR-exposed animals may be deficient in their ability to enhance the expression of MHC class I molecules on developing tumors. This alteration may, in part, account for the state of tumor susceptibility caused by UVR exposure.

Irradiation of skin with ultraviolet light (UVL) is capable of causing many biological and biochemical changes in this complex organ. One early consequence is the oxidation of epidermal plasma membrane cholesterol, causing the induction of a wide variety of photoproducts. It is well recognized that some oxygenated sterols possess potent biological activity on mammalian cells by their ability to inhibit endogeneous mevalonate and cholesterol biosynthesis. In the few immunological systems that have been studied, there is general agreement that lymphocyte function is altered in the presence of certain oxygenated sterols. Insight into the biochemical basis for altered lymphocyte function is lacking, as both afferent and efferent blockades have been suggested. These studies were undertaken to determine the effect of various oxygenated sterols (representing a number of known cholesterol-derived photoproducts) on the generation (afferent) and function (efferent) of cytotoxic T lymphocytes (CTLs). Cell-mediated immune responses which result in the generation of both alloantigen-specific and syngeneic tumor-specific CTLs were evaluated. (JMT)

C3Hf/HeN mice support the progressive growth of most transplanted syngeneic ultraviolet (uv) light-induced tumors following short-term uv exposure whereas nonexposed mice reject these tumors. Because an immunosuppressive role in uv-mediated tumor susceptibility might be suggested by these observations, a comparison of several immunological parameters has been conducted. These include antibody production, proliferation in response to antigenic and mitogenic stimulation, and the generation of cytotoxic effector cells by normal or short-term uv-exposed mice. The results indicate that short-term uv irradiation of mice does not result in any readily detectable alterations of the host's immune system other than the consistent loss of the antitumor response mediating rejection of the transplanted uv-induced tumor.

In this study we have characterized three series of clonal populations isolated from primary murine fibrosarcomas induced with three different doses of the chemical carcinogen, 3-methylcholanthrene (3-MCA). Clones were evaluated fro their in vivo growth rates after transplantation into normal syngeneic animals, and for immunological cross-protection toward clones derived from the same tumor. A pattern of reactivity emerged from these studies which supports, at the single-cell level, existing theories regarding the correlation between the inducing dose of chemical carcinogen and the antigenicity of the resulting tumors. Clones from tumors induced with 10 mg of 3-MCA were found to be less tumorigenic than clones from tumors induced with 5 mg of 3-MCA. The 5-mg clones were in turn less tumorigenic than the 1-mg clones, all of which grew rapidly in normal animals. Related clones from each tumor were found for the most part to be immunologically noncross-reactive with other clones from the same tumor, suggesting that subpopulations of tumor cells expressing different tumor-specific transplantation antigens (TSTAs) may reside within single primary tumors. We have used these observations to formulate an hypothesis for the origin of antigenic heterogeneity in 3-MCA-induced tumors and as the basis for a discussion of the relationship between cell transformation and the appearance at the cell surface of tumor-specific transplantation antigens.

The majority of skin tumors induced in mice by ultraviolet (UV) light are rejected when implanted into normal syngeneic recipients. Subcarcinogenic levels of UV light exposure render the normally resistant mice susceptible to tumor challenge. The immunoregulatory effect of UV light appears to be additive, since the growth rate of a tumor transplant is dependent upon the length of UV exposure administered prior to implantation. This suppressive influence does not appear to be directly mediated by the UV light, because the amputation of UV-irradiated tail skin allows for a retention of tumor resistance in otherwise tumor-susceptible hosts. UV-irradiated mice could also be immunized against UV tumors, which suggests that immune recognition of tumor-specific transplantation antigens has not been inhibited. The ability of UV exposure to alter normal immunological reactivity to UV-induced tumors is possibly an integral factor in the mechanism underlying UV carcinogenesis.

Experiments were conducted to determine the distribution and function of common tumor antigens shared by ultraviolet light (UV)., benz[a]pyrene (BP)-, and methylcholanthrene (MCA)-induced tumors. When lymph node cells were removed from UV, BP, or MCA tumor-immune mice and held in tissue culture for

The levels of NCMC activity residing in the spleens of normal and UV-irradiated mice (subsequent to augmentation with polyinosinic.polycytidylic acid [poly I.C]) were evaluated using tumor target cells from both lymphoid and solid tumor sources. Early in the UV-irradiation protocols a low-level, transient depression in NCMC function was detected. The levels of NCMC activity in mice that had received daily UV-exposures for a period of 5-10 weeks, however, were found to be equivalent to, or greater than, those detected in normal mice. Furthermore, regressor and progressor tumor cell lines that had been cloned from individual UV-induced tumors exhibited low, but similar, levels of sensitivity to NCMC cells obtained either from normal or from UV-irradiated mice. Poly I.C treatment of normal and UV-irradiated mice was found to have no effect on the outcome of subsequently implanted UV-induced regressor tumors; normal and poly I.C pretreated normal mice rejected the tumor implants, although both untreated and poly I.C pretreated, UV-irradiated mice grew the tumors at equivalent rates.

When normal mice are exposed for short periods to ultraviolet light (uv), they support the progressive growth of transplanted syngeneic uv-induced tumors. Normal nonirradiated mice almost always reject these tumor implants. The uv-mediated suppression of the antitumor response can be adoptively transferred to normal syngeneic mice with lymphoid cells derived from short-term uv-irradiated donors. Transfer of the suppressive effect is dosage dependent and also appears to require the presence of viable T lymphocytes. Suppressive activity was observed in both the spleen and thymus of uv-irradiated donors. In the preceding paper we have established that uv irradiation does not cause a general depression of testable immune functions. Collectively these data suggest that short-term uv irradiation of mice leads to an increase in suppressor cell activity, thereby causing an inhibition in the host's ability to respond to an antigenic uv-induced tumor. The possible role of this phenomenon in the mechanism of uv carcinogenesis is discussed.

The exposure of animals to ultraviolet radiation (UVR) can result in dramatic alterations to their immunologic potential. Loss of ability to be contact-sensitized to skin-reactive chemicals applied to UVR-exposed surfaces, and an enhanced susceptibility to tumors induced by UVR represent two well-documented effects of such exposure. The skin Langerhans' cell (LC) is a cell type, having antigen presentation capabilities, which is functionally inactivated by UVR. The localized loss in the ability to induce a contact hypersensitivity (CS) response and the early events associated with the acquisition of a tumor-susceptible state have been hypothesized to involve LC inactivation by UVR. In this report we have investigated the relationship between the UVR-mediated loss of CS responsiveness and antigen-presenting cell (APC) function by LC following in vivo exposure of animals to UVR. The UVR-mediated loss of CS responsiveness was found to be both time-dependent and dosage-dependent, but the loss of epidermal APC function following the UVR exposure of dissociated epidermal cells or skin was immediate and dosage-dependent. The lack of time dependency associated with the loss of epidermal APC function may be due to the nature of the assay system being employed. Add-back experiments, using the proliferation of purified antigen-primed T-cells as a read-out system to evaluate APC function, require that the accessory cell be totally functional. Initiation of CS responses may still be possible, however, with LC that are partially UVR-inactivated. Lymph-node-associated and circulating accessory cells could be integrated into the response, providing any necessary components that the UV-inactivated LC lacks. We tested this possibility and conclude from these studies that this is indeed a viable possibility. Our results, therefore, provide a possible explanation for apparent differences in LC UVR susceptibility observed when in vitro and in vivo assays are employed.

It has been previously reported that mice exposed to ultraviolet (UV) radiation exhibit a decrease in splenic antigen-presenting cell (APC) function. The results presented here confirm this observation and further demonstrate that animals exposed daily to UV for extended periods of time (5 weeks instead of 6 days) no longer exhibit this depressed capability. In spite of the depression in splenic APC activity found in 6-day UV-irradiated mice, lymph node APC function from these same animals was elevated compared with that found in the lymph nodes from normal animals. Lymph node APC activity in animals that were splenectomized prior to the UV irradiation, however, was not enhanced over controls. Treatment of animals with a chemical irritant (turpentine) also caused a depression in splenic APC function without modifying lymph node activity. Collectively, our findings suggest that the observed decrease in splenic APC activity, found after the first week of UV exposures, may be attributable to the migration of splenic APC to peripheral lymphoid tissue which drain the site of epidermal inflammation.