How is the Immune System Suppressed by Cancer

Direct Suppression/Inactivation of Oxygen Radicals:

Oxygen radicals from various different oxidases, including xanthine oxidase (XO) and NADPH oxidase (NADPHO) in macrophages and lymphocytes, as well as the circulation in the serum of XO, are responsible for the production of toxic substances such as peroxynitrite, OH radicals, hydrogen peroxide, etc. which are toxic to foreign proteins, bacteria, viruses, and cancer cells. This ability to produce large amounts of oxygen radicals is not seen in cancer cells themselves, but also in the cancer patients’ immune cells. They are weakened against cancer cell attack, partially because of the nitric oxide (NO) released by tumor cells.   Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells. However, since XO is inhibited in cancer patients from NO generated by tumor cells and most likely other factors not yet known, the production of hydrogen peroxide that would normally destroy a cancer cell is not produced. NO from eNOS in cancer cells can travel through membranes and over long distances in the body. It has even been shown that cGMP is stimulated in the liver in colon cancer patients and this is most likely from growth factors and NO released from the tumor cells.  NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2. The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
                                           

One other important alteration by nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface. This is normally an early stage for toxicity against bacteria, or “foreign” substances. However, this inability of binding alters this form of toxicity too.

Inhibition of inducible Nitric Oxide Synthase (iNOS): In macrophages, leukocytes and T-killer cells, the production of a fast generated NO from iNOS causes a very fast reaction with superoxide radicals from oxidases. It is enhanced by free iron, and is responsible for the toxicity from these cells. One of these toxic products generated is peroxynitrite. When the iNOS is down regulated or inhibited, or the oxygen radicals totally suppressed, there is a tremendous reduction in toxicity to almost null in some cases.
                                    
Binding of iron also affects this toxicity. NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.