Mesothelioma Information - Types of Mesothelioma
The anatomic location at which local production of IL-12 facilitates the priming of an immune response is not clear, but there are several possibilities. First, transfectant tumor cell products could reach the draining LNs and lead to effective priming. At the LN, tumor antigen may be presented in one of two ways. Uptake of tumor antigen and cross-presentation via the major histocompatibility complex (MHC) class I pathway has been demonstrated in other systems (41), and in our model this process may be rendered more effective in the context of IL-12 secretion. We have evidence that MM antigens are cross-presented to CD8+ cells in the LNs draining the tumor site (52). Alternatively, tumor antigen may be directly presented to LN T cells by the transfectant cells, the activation process again being facilitated by increased local IL-12 (42). A third possibility is that the transfectants directly activate tumor-reactive T cells at the transfectants' site of injection.
T cells from mice challenged with AB1-IL-12 produced significantly higher amounts of IFN- upon activation than did
those inoculated with the parental tumor, indicating a more Th1-type response. This result correlates with the well-documented property of IL-12 as a potent inducer of IFN- production by NK and T cells (16, 17). IL-12 also augments the proliferation of activated NK and T cells, and enhances NK and CTL activity (12), properties that further contribute to the antitumor activity of this cytokine, although as already discussed, no role for NK cells has been shown in anti-MM immune responses. Apart from inducing Th1 differentiation, it has been shown that IL-12 treatment can reverse suppression of IFN- production by T cells and correlates with tumor rejection (21). It is interesting to note that in our murine model of nontransfected MM, tumor-infiltrating lymphocytes produce messenger RNA for IFN- in the early stages of tumor development, but that this becomes undetectable as tumors progress (43). This loss of IFN- production may be an important factor in the relatively weak immunogenic nature of this tumor, and the IL-12 transfectant may lead to reversal of this trait.
The local production of the IFN- by infiltrating T cells within the tumor milieu could have other positive effects on the tumor environment. IFN- upregulates MHC class I and II antigen expression on APCs (44) and on some other cell types, thus facilitating antigen presentation. Interestingly the transient AB1-IL-12 tumors in our study not only contained a large T-cell infiltrate, but also showed a more widespread pattern of class II MHC antigen expression than did parental tumors. It is unlikely that the AB1-IL-12 transfectant, via IFN- production, induced increased class II antigen expression on the tumor cells, since IFN- does not induce the upregulation of class II antigens on MM cells in vitro (data not shown). In addition, the immunohistology of MM tumors indicates that the number of tumor cells does not correlate with the degree of staining for MHC class II antigens, making it more likely that the class II-bearing cells within the tumor mass are infiltrating macrophages, as previously described (45), or possibly dendritic cells, which could potentiate CD4+ cell responses within the tumor.
This is important because although we have shown that CD8+ cells are the effectors against MM tumors, CD4+ cells may provide help in maintaining or prolonging the CD8+-cell response, thereby contributing, albeit indirectly, to the efficacy of the antitumor response. IFN- is also one of the components involved in the induction of NO production by cells such as macrophages (46, 47). This compound has cytostatic/cytotoxic activity against tumor cells (48), and has been shown to directly contribute to the antitumor properties of IL-12 (51). Because macrophages are the predominant infiltrating leukocytes in MM tumors, it is possible that this pathway is also active in rejection of the IL-12 transfectant. Thus, once an immune response has been induced, the production of IL-12, either locally or in the LNs, may initiate a cascade of inflammatory signals that facilitates lymphocyte recruitment to the tumor site and enhances effector function.
Mesothelioma Information
Types of mesothelioma include: pleural mesothelioma, peritoneal mesothelioma and pericardial mesothelioma. Causes of mesothelioma have been limited to asbestos exposure. There are 2,000 to 3,000 new cases of malignant mesothelioma reported each year in the United States alone. Although malignant mesothelioma is viewed to be a somewhat rare type of cancer, the disease is believed responsible for an estimated 200,000 deaths worldwide.
Early mesothelioma detection can allow for more flexibility in terms of selecting a mesothelioma treatment option; however, no mesothelioma treatments have had success in combating the rare cancer.