Prostate cancer's one-two punch
http://www.100md.com
《实验药学杂志》
Tumors can avoid immune destruction despite being invaded by tumor-specific CD8+ T cells. On page 1257, Bronte et al. describe one way that prostate tumors subdue T cells—they make two enzymes that combine forces to cripple T cell signaling components.
Inducible nitric oxide synthase (NOS2) (brown) helps subdue CD8+ T cells in a human prostate tumor.
Tumors use a variety of tactics to avoid attack by cytotoxic CD8+ T cells; one is to establish an inhospitable environment that inhibits T cell activation. In recent mouse studies, myeloid suppressor cells infiltrated tumors and set up an inhibitory environment, apparently by making two enzymes—arginase and nitric oxide synthase 2 (NOS2).
Both enzymes can inhibit T cell functions independently. But when expressed together, the enzyme duo triggers a cascade of reactions that culminates in the production of peroxynitrite—an oxidizing agent that nitrates tyrosine residues on proteins. Tyrosine nitration blocks the tyrosine phosphorylation events required for T cell activation and promotes apoptosis.
Increased expression of both arginase and NOS2 in human prostate tumors has been reported, but their affect on tumor-infiltrating T cells has never been directly studied. Bronte and colleagues now show that CD8+ T cells in human prostate tumors failed to up-regulate the activation markers CD25 and CD69 in response to mitogenic stimulation. Activation was restored when both arginase and NOS2 were inhibited. This occurred even without exogenous stimulation, suggesting that the reawakened T cells were responding to in situ–presented tumor antigens.
The need to inhibit both enzymes to reactivate the T cells, and the presence of nitrotyrosine-positive cells in the tumor tissue, pointed to tyrosine nitration as the key to the T cell inhibition in this model. The authors are now trying to understand what triggers the expression of these enzymes in tumors and whether the same mechanisms operate in other human tumors.(Heather L. Van Epps)
Inducible nitric oxide synthase (NOS2) (brown) helps subdue CD8+ T cells in a human prostate tumor.
Tumors use a variety of tactics to avoid attack by cytotoxic CD8+ T cells; one is to establish an inhospitable environment that inhibits T cell activation. In recent mouse studies, myeloid suppressor cells infiltrated tumors and set up an inhibitory environment, apparently by making two enzymes—arginase and nitric oxide synthase 2 (NOS2).
Both enzymes can inhibit T cell functions independently. But when expressed together, the enzyme duo triggers a cascade of reactions that culminates in the production of peroxynitrite—an oxidizing agent that nitrates tyrosine residues on proteins. Tyrosine nitration blocks the tyrosine phosphorylation events required for T cell activation and promotes apoptosis.
Increased expression of both arginase and NOS2 in human prostate tumors has been reported, but their affect on tumor-infiltrating T cells has never been directly studied. Bronte and colleagues now show that CD8+ T cells in human prostate tumors failed to up-regulate the activation markers CD25 and CD69 in response to mitogenic stimulation. Activation was restored when both arginase and NOS2 were inhibited. This occurred even without exogenous stimulation, suggesting that the reawakened T cells were responding to in situ–presented tumor antigens.
The need to inhibit both enzymes to reactivate the T cells, and the presence of nitrotyrosine-positive cells in the tumor tissue, pointed to tyrosine nitration as the key to the T cell inhibition in this model. The authors are now trying to understand what triggers the expression of these enzymes in tumors and whether the same mechanisms operate in other human tumors.(Heather L. Van Epps)