The neuroimmune roles of indoleamine pathways in cancer

A Latin aphorism "Mens sana in corpore sano" implies that the correlation between mental and physical health has been known for thousands of years. This phenomenon has been observed in several diseases, such as cardiovascular diseases, autoimmune diseases, and cancer. Currently, cancer kills more than six million people each year and has become a heavily economic burden caused by the treatments. Miovic and Block reported that 5-26% of advanced cancer patients have major depression, and are prescribed with antidepressants. A new medical field named "psycho-oncology" is launched based on these clinical observations. In the field of psyco-oncology discusses both the effects of cancer on a person's mental health as well as the behavioral factors that may affect the progress of cancer. Serotonin is a major neurotransmitter contributing to the feeling of happiness, and there is a strong correlation between the serotonin level and depression. It has been shown that the serotonin level of cancer patients is significantly lower than that of healthy subjects. Serotonin is synthesized from tryptophan which is one of the essential amino acids for mammals. Dysregulation of tryptophan metabolic pathways could be responsible for developing depression symptoms in cancer patients. Tryptophan is metabolized through the kynurenine pathway by up-regulated indoleamine 2,3- dioxygenase (IDO) in cancers instead of the serotonin pathway used in neurons, resulted in the decrease of serotonin production. In addition, the intermediates and final product of the kynurenine pathway, such as 3-hydroxykynurenine (OHK) and quinolinic acid (QUIN), are potent neurotoxins. Increased levels of these neurotoxins may contribute to the apoptosis of astrocytes and other neurons, affect various networks in the brain, and result in depression symptoms or other mental disorders. The up-regulated kynurenine pathway in cancer patients not only strikes the survival of neurons and regulations of several networks in the brain, but impacts the antitumor immunity of T cells. The shortage of tryptophan inhibits the proliferations of CD8+ T cells and CD4+ T-helper cells. In addition, kynurenine could cause these T cells to apoptosis. It also has been reported that numbers and activities of T cells are highly correlated with the prognosis and survival of patients. Other than decreasing the numbers and functions of T cells, kynurenine also turns tumor microenvironment toward more immunosuppressive. Tryptophan is converted into 5-hydroxyl-L-tryptophan (5-HTP) by tryptophan hydroxylase (TPH) and its cofactor tetrahydrobiopterin (BH4) under the normal physical condition. However, the BH4 is also the cofactor of nitric oxide synthase (NOS) which could be induced by proinflammatory cytokines, such as interleukin-6 (IL-6), in the tumor microenvironment. Inducible nitric oxide synthase (iNOS) competes BH4 with TPH and causes the lower production of serotonin and other neurotransmitters, both worsen the depression symptoms in cancer patients. On the other hand, BH4 helps iNOS to convert arginine to nitric oxide (NO) that is further metabolized into reactive nitrogen species (RNS), such as peroxynitrite. These RNS cause post-translational modifications of proteins, and the RNS-modified cytokines would affect the recruitments of immune cells and antitumor immunity. In overall, the metabolism of tryptophan significantly influences the synthesis of serotonin and generation of kynurenine, and is closely correlated to the cancer-induced depression and immunosuppression. Hence, the roles of indoleamines, such as tryptophan and serotonin, and their related pathways will be discussed in the following. Moreover, how these molecules modulate the immunity and mood in cancer patients will also be covered.