Tumors are analogous to tissue graft in that they are most likely recognized by the immune system, yet through either a tolerance or evasion mechanism, do not elicit a destructive immune response. Clinical evidence shows that individuals with suppressed immune systems are most susceptible to tumor appearance. However, animal experimentation indicates that immune surveillance is directed toward viruses rather than tumors. Because tumors do appear and grow within a host, they must somehow evade an immune response. Tumors may be characteristically poor antigen-presenting cells (APCs), contributing to their nonimmunogenicity. Immune response requires cell-surface molecules such as the co-stimulator, B7, molecule or cytokines presented by these APCs, especially if the tumor lacks MHC class II antigens. Tumor cells may also lack necessary adhesion molecules such as LFA-1 and -3 or ICAM-1 or present antiadhesive molecules. In addition, like trophoblast cells, they may secrete immunosuppressive TGFb or shed surface antigens ,
In gestational trophoblastic disease (GTD) and in choriocarcinoma in particular, the malignant trophoblast, like healthy trophoblast, continues to evade the maternal immune response. However, the methods and mechanisms of avoiding this response may differ. For example, in a study by Sunderland , 40-70% of the tumor cells studied expressed MHC I antigens, and most of these cells did not express the paternal, polymorphic HLA antigenic determinants (MHC II). Indeed, reports of a specific inhibitory substance to the paternal HLA allotype in patients with GTD have been documented . These studies present a strong case for lack of recognition as nonself. Also, some, but not all, choriocarcinoma cells present HLA-G, a surface antigen presented by normal trophoblast cells. However, other studies indicate that there are no known tumor antigens in GTD that differ from those in normal trophoblast for which an immune response could be elicited .
TLX antigens may also be present in choriocarcinoma tissue. If, as stated above, antitrophoblast blocking antibodies are involved in the protection of the trophoblast from the maternal immune response in normal pregnancy, the expression of antigens by choriocarcinoma cells must be important to their survival. While patients with gestational choriocarcinoma rejected skin grafts from inappropriate "first-set" time interval skin from unrelated donors, they tolerated grafts from their husbands or the children of these pregnancies for extended periods of time , In fact, it has been postulated that choriocarcinoma tissue could be supported by response to trophoblast antigens , Therefore, the presence of similar antigens on cells derived at least in part from the paternal genome confer immunity to further reaction against these antigens. Conversely it suggests lack of frank maternal immunosuppression.
A common product of both normal trophoblast and choriocarcinoma is the secretion of GM-CSF and CSF-1. All three classical choriocarcinoma cell lines (JEG, JAR, and BeWo) have been shown to secrete these factors. Antibodies to these substances appear to have an autocrine inhibitory effect on the proliferation of choriocarcinoma cells. However, CSF-1 may be linked to the synthesis of hCG which itself has an immunosuppressive effect on the region surrounding the trophoblast . This is seen also in the early placenta, where incubations with both G-CSF and M-CSF stimulated an increase in hCG secretion .
As in normal trophoblasts, the secretion of IFNs may also play a part in local immunosuppression. In both the normal and malignant cases, trophoblast IFN-a and -/3 inhibit proliferation. In fact, in a comparison of normal and BeWo cell lines with the addition of 1000 IU/ml of these IFNs, they were much more effective at inhibiting choriocarcinoma cells. In addition, IFN-/3 has been shown to inhibit the proliferation of T- and B- lymphocytes, contributing to the immunosuppression of the fetoplacental unit .
EPF was discussed as a product of normal pregnancy, but may also be a marker for the diagnosis of malignant trophoblastic tumor. EPF has been detected in the serum of patients with choriocarcinoma and invasive mole by the rosette inhibition test, lending evidence to the altered immune environment present in GTD ,
As mentioned in the introduction, the state of the immune system may have some correlation with the prevalence of cancer. Based on this argument, if pregnancy would have contributed to the suppression of the maternal immune system, one would expect a heightened susceptibility to cancer during pregnancy. However, the immune system is not suppressed during pregnancy, but rather altered, and may actually contribute to a relative protection against tumor burden. A number of theories have been proposed to explain the role of the immune system in the control of cancer. Evidence of immune intervention in cancer includes postmortem data suggesting more tumors than actually are manifested, presence of lymphoid infiltrate in tumors, spontaneous tumor regression, tumor frequency during immune suppressed life stages such as neonatal period and old age, and increased tumor frequency in immunosuppressed individuals .
A particularly striking study indicating the immune protection of pregnancy has been done on Non-Hodgkin's lymphoma (NHL) patients . This research indicates a much lower occurrence of NHL during pregnancy among reproductive age women. In animal studies, 36-75% of rats inoculated with virally-
induced lymphoma during pregnancy did not develop tumors and 20-54% developed tumors half the size of controls. In addition, pregnant rat sera was shown to have an inhibitory effect on the growth of lymphoma cells in vivo and in vitro.
A related study  does not suggest tumor immunity, but does argue against immune suppression by showing no differences in progression of lymphoma between pregnant and nonpregnant patients. Patients diagnosed with both Hodgkin's disease and NHL were studied and results indicated similar outcomes for both pregnant and nonpregnant subjects. Studies of breast cancer have also provided evidence for the immune protective characteristics of pregnancy. Previous successful pregnancy has been linked with protection against breast cancer later in life. T cells from biparous women, but not T cells from nulliparous women or men, specifically proliferated in response to core peptide sequences of a human breast cancer-associated mucin (MUC-1). Two of the nulliparous women were retested during the first trimester of their first pregnancy, and their T cells proliferated specifically in response to MUC-1 mucin. These observations support the hypothesis that immunization against MUC-1 peptide epitopes during pregnancy may protect against breast cancer and such antibodies may a have a therapeutic role ,
One proposed explanation for the altered state of immunity observed in pregnancy is a change in cytokine response. This change involves a shift from the Thl paradigm of cytokine response to the Th2 pattern, from humoral to cell-mediated immunity. The results of this is that the preferential activation of either Thl or Th2 cells may cause an immune response alteration ,
In this chapter, we have examined the immune system in normal pregnancy as it compares to pathologic pregnancy such as GTD or concurrent cancer. From the available data, it appears that the immune reaction to the partial allograft during pregnancy is very complex and involves both tolerance and evasion from immune recognition. Further, it appears that when malignancy is present during pregnancy, specifically of the trophoblast through GTD, the changes in the trophoblastic tissue leading to the malignancy are not sufficient to reactivate the immune system. The only distinguishing features of immunologic activity between normal trophoblast and choriocarcinoma so far described are the reduction in the production of PAPP-A and the presence of class I MHCs , neither of which elicit an immune response. An immune reactivation occurs in most instances of failing pregnancies, which are, in general, rejected through spontaneous abortion. This raises the possibility that GTD may be a very unique tumor. Its ability to survive may be somewhat linked to its sensitivity to treatment by chemotherapy indeed GTD, in practical terms, can be treated successfully in almost 100% of cases. In other instances of cancer during pregnancy, despite the onslaught of growth promoters, which are known to have a major role in cancer development and promotion, and an altered immune response, tumors actually do not progress as expected. In certain cases, pregnancy actually has a protective effect both in the short and long-term. Such a beneficial effect would require the presence of certain protective mechanisms, some of which have recently have been identified. Whether pregnancy actually confers an immune advantage to patients with cancer compared to nonpregnant patients remains an open question. These protective factors may operate to guard the immune system from being affected as is the case in cancer, and through production of specific powerful compounds, would prevent or limit significant cancer cell proliferation. We and others have recently discovered evidence for such protective mechanisms [45-46]. In our studies, we have demonstrated that some of the active factors, embryo derived proteins, specifically control cancer cell and virally induced transformed cells proliferation without affecting normal cells . One of the active compounds was recently sequenced and found to be a novel oligopeptide (Barnea and Leavis, unpublished observations). Whether this oligopeptide is involved in modulating the immune response remains to be established as well. Overall insight into the various protective mechanisms present during pregnancy and which in certain instances confer long term protection against malignancy, are very fruitful avenues of investigation which should be pursued actively. Identification of these compounds and the mechanisms involved will have a major impact on the both the understanding of neoplastic processes and the development of efficacious therapeutic tools against these serious and often fatal condition.
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