Tumor-induced immunosuppression

Lejeune, R, Lagadec, R, Onier, N., Pinard, D., Okshima, H., and Jeannin, J.F. (1994). Nitric oxide involvement in tumor-induced immunosuppression. J. Inununol. 152, 5077-5083. 

Three lipids A have been more intensively studied in animal models, all of them having indirect effects, mediated in vivo by the immune system. For two of them, DT-5461 and ONO-4007, TNF-a is an important mediator acting at the vascular level that provokes tumor necrosis. For the third one, OM-174, the treatment induces the accumulation of IFN-y and EL-1 P in tumors, which activate NOS II transcription in tumor cells that produce autotoxic NO, which then provokes the apoptosis of tumor cells. At the same time this treatment inhibits the production of TGF-pi by tumor cells which reduces the TGF-pi induced immunosuppression and enhances NO production. Acquired immune response, probably completes the tumor regression started by the apoptosis process and, most probably induces specific memory. 

Direct tumor-inducing effects of the glucocorticoids are not known, but the particular risk that malignancies in patients undergoing immunosuppression with these or other drugs will spread more rapidly is a well-recognized problem. 

Would it be possible to reverse this tumor-induced dominant immunosuppressive milieu There is some preliminary evidence suggesting that appropriate engagement of TLR may offer an avenue for breaking tolerance. In vitro studies have shown that stimulation of TLR-4 or TLR-9 on DCs can block the immunosuppressive effect of Tr cells on T effector cells (109). More recently, animal model studies have further provided support to this concept, where sustained TLR stimulation was shown to reverse the immunosuppressive effects of the tumor-induced Tr on anticancer immune responses... 

The suppression of T cell-mediated immunity by UV radiation appears to be a prerequisite for the outgrowth of UV-induced tumors in mice and is also manifested by an impaired ability to respond to contact sensitizing agents. Feeding AGE improved the impairment of contact hypersensitivity in hairless mice exposed to UVB (280-320 nm) radiation [41]. The modulation of UV-induced immunosuppression by AGE has been suggested to involve antagonism of the role of cis-urocanic acid, a natural photoproduct believed to participate as an immunogenic mediator. 

The present primary mode of therapy for these diseases involves the use 5-amino-salicylate (5-ASA) products. Often patients require additional medications, including corticosteroids, to help induce remission and various immune modulators, such as azathioprine, 6-mercaptopurine or methotrexate, to maintain remission. In Crohn s disease certain antibiotics, such as metronidazole and ciprofloxacin, and infliximab Remi-cade), an anti-tumor necrosis factor-a(TNFa) antibody, also have been used. The pharmacology of antibiotics, immunosuppressive drugs, and corticosteroids is discussed in Chapters 43,57, and 60, respectively. 

Toxicities are numerous and include nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hyperkalemia, altered mental status, seizures, and hirsutism. Cyclosporine causes very little bone marrow toxicity. While an increased incidence of lymphoma and other cancers (Kaposi s sarcoma, skin cancer) have been observed in transplant recipients receiving cyclosporine, other immunosuppressive agents may also predispose recipients to cancer. Some evidence suggests that tumors may arise after cyclosporine treatment because the drug induces TGF-B, which promotes tumor invasion and metastasis. 

Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis Djouad, F., Fritz, V., Apparailly, F., Louis-Plence, P., Bony, C., Sany, J., Jorgensen, C., Noel, D. (2005). Arthritis Rheum, 52... 

The precise role of immunological surveillance in tumorigenesis is not well dehned for the majority of malignancies. The occurrence of a unique spectrum of malignancies in immunosuppressed individuals suggests either that immune surveillance is only important in certain tumors or that the duration needed to see an increased incidence of many more common tumors (e.g., colorectal, breast, lung, or prostate carcinomas) is not reached. Suppression of T cell mediated immunity has, however, been unequivocally associated with an increased incidence of certain mahgnancies. In patients with profound defects in T cell immunity the time to tumor detection is often shorter than for cancers induced by other mechanisms. 

Although tumor induction has mostly been documented in patients treated for cancer, long-term cyclophosphamide treatment for non-neoplastic conditions can also increase the incidence of certain neoplasms. Whether this oncogenic effect is a consequence of drug-induced chromosomal aberrations rather than immunosuppression is unclear. An increased incidence of bladder cancers, skin cancers, and myeloproliferative disorders was found in a 20-year follow-up study of 119 patients with rheumatoid arthritis, and a high dose of cyclophosphamide (mean total dose of 80 g) was the main susceptibihty factor (47). 

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